The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Steven R Goodman; Daniel Johnson; Steven L Youngentob; David Kakhniashvili

doi:10.1177/1535370219867269

. 2019 Sep 4;244(15):1273–1302. doi: 10.1177/1535370219867269

The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Steven R Goodman ^1,^✉, Daniel Johnson ¹, Steven L Youngentob ², David Kakhniashvili ¹

PMCID: PMC6880150 PMID: 31483159

Short abstract

We provide a review of Spectrin isoform function in the cytoplasm, the nucleus, the cell surface, and in intracellular signaling. We then discuss the importance of Spectrin’s E2/E3 chimeric ubiquitin conjugating and ligating activity in maintaining cellular homeostasis. Finally we present spectrin isoform subunit specific human diseases. We have created the Spectrinome, from the Human Proteome, Human Reactome and Human Atlas data and demonstrated how it can be a useful tool in visualizing and understanding spectrins myriad of cellular functions.

Impact statement

Spectrin was for the first 12 years after its discovery thought to be found only in erythrocytes. In 1981, Goodman and colleagues¹ found that spectrin-like molecules were ubiquitously found in non-erythroid cells leading to a great multitude of publications over the next thirty eight years. The discovery of multiple spectrin isoforms found associated with every cellular compartment, and representing 2-3% of cellular protein, has brought us to today’s understanding that spectrin is a scaffolding protein, with its own E2/E3 chimeric ubiquitin conjugating ligating activity that is involved in virtually every cellular function. We cover the history, localized functions of spectrin isoforms, human diseases caused by mutations, and provide the spectrinome: a useful tool for understanding the myriad of functions for one of the most important proteins in all eukaryotic cells.

Keywords: Spectrin, Fodrin, Subcellular Function, Interactome, Spectrinome

Introduction

The discovery of nonerythroid spectrin in 1981, by Goodman and colleagues¹, has led to a large number of publications describing first its structure and functions within the plasma membrane and cytoplasm and then within the nucleus of eukaryotic cells. As spectrin contributes 2-3% of the total protein in eukaryotic cells^2–4, is found associated with every organelle and major cytoskeletal component⁵, and has its own E2/E3 chimeric ubiquitin conjugating ligating activity^6–9, it should come as no surprise that this ubiquitous scaffold protein belies a myriad of cellular functions that reside within the nucleus and cytoplasm and integrate these cellular compartments. In this minireview, we introduce the concept of the spectrinome, or spectrin interactome, and explain how this is a useful construct to think about its integrative functions. We will raise questions that should keep those interested in spectrin busy for decades to come. We begin the discussion by presenting the earliest discovered spectrin that was found within the erythrocyte on the cytoplasmic surface of the plasma membrane.

The Erythrocyte Membrane Skeleton

Erythrocyte spectrin was first isolated from human red blood cells (RBCs) by Marchesi and Steers Jr. in 1968¹⁰. They said “The functional role of this protein is unknown, but it appears to be involved in maintaining the structure of the red cell membrane”. Over the next 20 years, the structure and function of the RBC spectrin membrane skeleton was elucidated (Figure 1). This membrane skeleton does, as suggested by Steers and Marchesi, provide structural integrity to the erythrocyte, but also is responsible for its elasticity and flexibility that allows a biconcave disc of 8 μm diameter to continuously pass through a circulatory system that narrows to less than 2 μm in venules.

Figure 1. — The Red Blood Cell Membrane Skeleton

This figure provides a view of the cytoplasmic surface of the Red Blood Cell (RBC) plasma membrane. The spectrin membrane skeleton shown in this diagram provides the RBC with its shape, elasticity, and deformability. It provides the bilayer with structural stability and controls the lateral mobility of transmembrane proteins. The interactions are discussed in the text. Spectrin tetramers crosslink actin assemblies containing short actin protofilaments, containing 13 -14 g-actin (Act) monomers, tropomyosin (TM), and tropomodulin (TMOD), into what appears as a hexagonal array upon negative staining and EM of expanded membrane skeletons. The interaction of spectrin and actin filaments are strengthened by association of protein 4.1 (4.2) and adducin (Add) to the tails of beta spectrin (βSp). These are referred to as horizontal interactions. Spectrin associates with the membrane by association of βSp with ankyrin (Ank) which in turn associates with a band 3 (B3) complex which also includes protein 4.2 (4.1) and Glycophorin A (GLA). The tails of spectrin are associated with the membrane via an interaction with 4.1 which in turn binds to glycophorin C (GLC). These are the so-called vertical interactions. This figure was adapted Goodman et al⁹ with permission.

RBC Spectrin is composed of an α and β subunit of 280 kDa and 246 kDa respectively. The simplest form of RBC spectrin is an antiparallel αβ heterodimer, but on the cytoplasmic surface of the plasma membrane it primarily takes the form of an (αβ)₂ tetramer formed by head-to-head interaction of two heterodimers.^11,12 As such the two tail regions of the heterodimer are chemically equivalent and can bind and crosslink short actin protofilaments (∼14 g actin monomers long).^13–15 The binding of spectrin to these short actin protofilaments is strengthened by the binding of protein 4.1^16–19 and adducin^20–23 to the tail regions, each forming its own ternary complexes with spectrin and actin. Electron micrographs of spread membrane skeletons demonstrated a hexagonal array (Figure 1) with actin protofilaments at the vertices and center, interconnected by spectrin tetramers. The RBC spectrin tetramers isolated at low ionic strength and visualized by negative staining and electron microscopy appear as flexible rods that are 200 nm long^13–15. As will be discussed below these rods can condense to 55-65 nm. This provides the membrane skeleton and plasma membrane with its properties of elasticity and flexibility. The spectrin tetramers, and hence the membrane skeleton are associated to the bilayer through spectrin-ankyrin-band 3^24–28 (another early name for ankyrin was syndeins²⁵) and spectrin-4.1-glycophorin C interactions^29,30 (with accessory proteins) as shown in Figure 1.

Spectrin Isoforms

In 1981, Goodman and colleagues described “Spectrin-like” proteins in embryonic chicken cardiac myocytes (ECCMs), cultured mouse fibroblast 3T3 cells, and rat hepatoma HTC and HMOA cells.¹ They immunoprecipitated two peptides of 240kDa and 230 kDa apparent molecular weight from the ECCMs, with anti-RBC spectrin antibody. These spectrin-like proteins were stained with spectrin antibody on immunoautoradiography and generated similar chymotryptic peptides to the α and β subunits of embryonic chicken RBC α and β spectrin¹. Goodman’s description of nonerythroid spectrin was confirmed by multiple laboratories in 1982.^31–34 This seminal finding led to a large number of publications from many laboratories bringing us to our current understanding that it is present in all eukaryotic cells.

One of the first tissues that was explored for the structure, location and function of spectrin was brain.^33,35,36 Several laboratories isolated brain spectrin that contained α and β subunits with apparent molecular weight of 240 kDa and 235 kDa.^33,35,36 Reiderer et al³⁷ prepared two antibodies against [1] mouse brain spectrin, which were isolated from an enriched fraction containing synaptic/axonal membranes, and [2] mouse RBC spectrin. They then cleaned these antibodies against the reverse antigen: [1] mouse RBC spectrin and [2] mouse brain spectrin isolated as described above.³⁷ These antibodies that had very high specificity to their own antigen were used by Reiderer et al³⁷ to determine localization of these two spectrin antigens in mouse cerebellum. What was found was that the brain spectrin antibody stained axons and presynaptic terminals, while the RBC spectrin antibody stained specifically the soma, dendrites, and post synaptic terminal of all neurons.³⁷ This was the very first description of distinct spectrin isoforms, which Reiderer et al called brain spectrin 240/235 and brain spectrin 240/235E (for erythroid).³⁷ As will be described below, today these isoforms would be called αSpIIΣ1/βSpIIΣ1(nonerythroid spectrin isoform) and αSpIΣ1/βSpIΣ2 (the erythroid spectrin isoform). Over the next five to six years Goodman, Reiderer, Zagon, Zimmer and colleagues would go on to demonstrate that this differential localization was true for neurons throughout the central nervous system^5,37–43 and that these two isoforms had very different expression during brain ontogeny.^44–46 The nonerythroid spectrin isoform was present at the earliest stages of prenatal mouse brain development and constantly increased during brain ontogeny while the erythroid spectrin isoform arose beginning in the second week of mouse brain postnatal development^44–46.

A major step in the localization of the brain spectrin isoforms was the first immuno-electron microscopic study on mouse cerebellum by Zagon et al.⁵ As described by Zagon et al,⁵ and shown in Figure 2, spectrin isoforms were compartmentalized as described by Reiderer el al.³⁷ At the electron microscope level of resolution, we found the spectrin isoforms not only on the cytoplasmic surface of the plasma membrane, but also on the cytoplasmic surface of all organelle membranes (nuclear envelope, endoplasmic reticulum, mitochondria, etc.). The spectrin isoforms were also in the cytoplasm crosslinking cytoskeletal elements (actin filaments, intermediate filaments and microtubules) to each other and to membrane surfaces. We also observed granular staining within the nucleus. Brain spectrin 240/235 was in the presynaptic terminal staining the plasma membrane, cytoskeletal structures and small spherical synaptic vesicles, while spectrin 240/235E was found in the post synaptic terminal associated with the plasma membrane, mitochondria, cytoskeletal elements and post-synaptic densities.⁵

Immunoelectron microscopy location of spectrin isoforms

Reiderer et al³⁷ provided the seminal study defining the existence of unique erythroid and non-erythroid spectrin isoforms. Zagon et al⁵ then reported the first immuno-EM study localizing these spectrin isoforms within neurons and glial cells of mouse cerebellar cortex. The red color shows the localization of αSpI/βSpIΣ2 and the blue color indicates the location of αSpII/βSpII. Figure was taken from Zagon et al⁵ with permission (Copyright 1986 Society For Neuroscience).

Today we know that there are two alpha spectrin genes, SPAT1 and SPTAN1, that encode the erythroid (αSpI) and nonerythroid (αSpII) spectrin isoforms respectively. There are also five beta spectrin genes SPTB, SPTBN1, 2, 4, 5 which encode the erythroid (βSpI) and nonerythroid (βSpII, III, IV, and V) spectrin isoforms. Table 1 gives the protein nomenclature, names in the literature, molecular weight, human gene symbol, and human chromosome locus for the seven spectrin genes and their products. Alternate splice forms of the spectrin genes give rise to isoforms indicated with the symbol Σ. Note that a common alternate name for the non-erythroid spectrin is Fodrin.⁴⁷ This name was coined when Levine and Willard found two axonally transported proteins of 240 kDa and 235 kDa apparent molecular weight that failed to react with spectrin antibodies.⁴⁷ Spectrin was given several other names before the recognition of its relationship to spectrin.

Table 1.

Spectrin Isoforms

Spectrin Protein Nomenclature	Names in Literature	Molecular Weight	Human Gene symbol	Human Chromosome
αSpIΣ1	α erythrocyte spectrin	280 kDa	SPTA1	1q23.1
αSpIIΣ1,2, 3, 4	Nonerythroid α spectrin, α spectrin II, α fodrin	280 kDa for Σ1	SPTAN1	9q34.11
βSpIΣ1	β erythrocyte spectrin	246 kDa	SPTB	14q23.3
βSpIΣ2	β erythroid spectrin	268 kDa
βSpIIΣ1,2	Nonerythroid β Spectrin, β spectrin II, β fodrin	275 kDa for Σ1	SPTBN1	2p16.2
βSpIIIΣ1		271 kDa	SPTBN2	11q13.2
βSpIVΣ1, 2, 3, 4, 5		288 kDa for Σ1	SPTBN4	19q13.13
βSpVΣ1		417 kDa	SPTBN5	15q21

Open in a new tab

The nonerythroid spectrin isoforms are found in all eukaryotic cells, except RBCs. The erythroid spectrin isoforms are found in RBCs, neurons, cardiac and skeletal muscle.^2–4,34,48 The spectrin tetramers are usually composed of either complexed erythroid α and β subunits or non-erythroid α and β spectrin subunits.⁴⁹ Clark et al demonstrated that a smaller percentage of spectrin tetramers in brain tissue are hybrid where αSpI complexes with βSpII, III, IV, or IV or αSpII complexes with βSp1Σ2.⁵⁰

Spectrin Structure

As described above, erythrocyte spectrin is found in situ primarily as (αβ)₂ tetramers, although higher order oligomers exist.⁵¹ This is also true for the nonerythroid spectrins.⁴ In both cases head to head linkage of two heterodimers forms a tetramer with chemically equivalent tail regions. As shown in Figure 3, the heterodimers contain α and β subunits that are antiparallel with the N-terminus of the β subunit and the C-terminus of the α subunit at the tail regions of the tetramer. The original protein sequencing of a segment of this αSPI followed by secondary structure determination defined a spectrin repeat unit of approximately 106 amino acids.⁵² Several X-ray crystallography studies^53–55 have indicated that the spectrin repeats maintain the 3 dimensional structure shown in Figure 3A. What is presented in this Figure are two adjacent αSPI repeats 16 and 17. Repeat 16 shown in Figure 3 A contains three α helices, where Helix A (dark blue) and C (green) are parallel and B (light blue) is antiparallel. As can be seen in the illustration Helix B is a little longer than the other two helices and is kinked in the middle due to a conserved proline residue. Repeat 16 and 17 are associated through the association of Helix C in repeat 16 with Helix A in Repeat 17 (also colored green to show the continuity). Helix A and B in each Repeat are associated by coiled flexible regions. The individual spectrin repeats are separated by regions which can bend in αSPI and βSpI and less so in αSpII and βSpII. Atomic Force Microscopy has indicated that the erythrocyte spectrin molecule can condense down to approximately 55-65 nm,^56,57 and it has been recently suggested that it does so by creating a quaternary structure resembling a Chinese finger trap.⁵⁸ The ability of erythrocyte spectrin tetramers to condense and expand, from 55 to 200 nm is what provides the erythrocyte membrane skeleton with its properties of elasticity and flexibility.

The complete sequence of mouse and human erythrocyte αSpI and βSpI^59–61 and nonerythroid αSpII and βSpII^47,62–65 have been determined by cloning and DNA sequencing. αSpI, the α subunit of human αSpIΣ1/βSpIΣ1, contains 2419 amino acids and has a mass of 280,014 daltons. As shown in Figure 3b, αSpI has 20 spectrin canonical repeats while repeat 21 contains EF Hand domains between residues 2271 and 2386. EF Hand domains bind Ca²⁺.⁶⁶ Between repeat 9 and 10 there is an SH3 domain involved in signal transduction.^67–69 Interestingly, in repeat 20 there is a E2 ubiquitin conjugating site with 70% identity to all known E2 active sites and the canonical cysteine (C2071) that can transfer ubiquitin to itself in a lysine rich segment of repeat 21.^6–9 Spectrin’ s chimeric E2/E3 ubiquitin conjugating/ligating activity was demonstrated to target other spectrin binding proteins (ankyrin, protein 4.1, 4.2, the anion transport channel and an unknown protein gi13278939) as well.^70,71 This will be discussed in far more detail below. αSpI also has an N-terminal sequence that does not have the typical repeat structure (labeled 0) that associates with the C-terminal sequence of βSpI (labelled 17) creating the head-to-head linkage creating the tetramer.

The βSpI sequence, beta erythrocyte spectrin βSpIΣ1, contains 2,137 residues and has a molecular weight of 246,468 daltons. βSpIΣ1has 16 canonical repeats where repeat 17 has a pleckstrin homology (PH) domain.⁷² PH domains are involved in cell signaling, cytoskeletal organization and phosphinositide binding. Goodman’s laboratory found that the N-terminal, non-repeat, segment of βSpI contains the actin-binding domain (ABD).⁷³ They demonstrated that residues 47 to 186 contains the binding site, and that this sequence was highly conserved in other actin binding proteins such as dystrophin, α-actinin, and many others.⁷³ Consistent with this seminal work, later studies confirmed the ABD and found two Calponin Homology (CH) domains within this ABD region, which appear to bind f-actin.⁷⁴ CH1 (residues 1-160) can bind f-actin on its own; but CH2 cannot bind f-actin on its own, unless the first 20 amino acids are truncated (leaving residues 191-280).^75–77

αSpII, or nonerythroid spectrin αSpIIΣ1, contains 2,472 residues and has a molecular weight of 284,539 daltons. As shown in Figure 3C, αSpIIΣ1 has 21 spectrin repeats with similar EF Hands, SH3, E2/E3-Ubiquitin-Conjugating/Ligating and target sites as αSpιΣ1 described above. What is unique is the Calmodulin Binding Loop (CBL) that is a 36 amino acid insert that has a Ca²⁺-dependent calmodulin binding site and can be cleaved by calpain and caspases 2, 3 and 7.^78–83 This cleavage is blocked by phosphorylation of tyrosine1176.^80,81 The overall sequence identity for αSpIIΣ1 and αSpιΣ1 is approximately 60%.

βSpII or nonerythroid spectrin βSpIIΣ1 contains 2,364 residues and a molecular weight of 274,699 daltons. βSpII, like βSpI, has 17 spectrin repeats with a similar ABD and PH. They share about 60% sequence identity. The C-terminus of βSpIIΣ1 extends 207 amino acids beyond the end of βSpI. Ma et al⁶⁴ who performed the sequence analysis on mouse found a hydrophobic section of βSpIIΣ1, that has very high sequence homology with the heme binding domain of globins. This laboratory went on to demonstrate that non-erythroid spectrin has the ability to bind hemin in vitro.⁶⁴ This observation could be of major importance to Oxygen and Nitric oxide localization and function intracellularly and is worthy of follow up.

Constructing the Spectrinome

As spectrins are known to be multifunctional scaffold proteins located both in the nucleus, cytoplasm and all cytoplasmic facing membranes (including the plasma membrane), we felt it would be of great value to build a spectrinome using existing human interactome data and then placing the proteins within either the nuclear or cytoplasmic compartments using the human atlas data.

The Homo sapiens gene-gene interaction and Homo sapiens protein-protein interaction files were downloaded from the Reactome Pathway Database (https://reactome.org/).⁸⁴ In addition to the Reactome files, we downloaded the Hallmark and C2 pathways from the Molecular Signatures Database from the Gene Set Enrichment Analysis set created by the Broad Institute (http://software.broadinstitute.org/gsea/msigdb/collections.jsp).⁸⁵ The files were combined to create a list of all Homo sapiens interactions.⁸⁶ We created a program in C++ to collect all interactions that involve SPTA1, SPTAN1, SPTB, SPTBN1, SPTBN2, SPTBN4, or SPTBN5. Each subset of reactions were saved into a csv file. The seven files were then combined to create a master list of all seven spectrins. These files were used to create an edge and vertex list for each interaction graph. The graphs were created in R using ggnet2. Secondary interactions were gathered from the reactome database using the previous C++ program, and used to create secondary interaction graphs for SPTA1 and SPTAN1. Locations of each protein inside human cells were extracted from the Human Protein Atlas (https://www.proteinatlas.org/).⁸⁷ The proteins were separated into four categories for the interaction graphs: nucleus, cytoplasm, both areas, and spectrin.

The 1st order interactions and 2nd order interactions for SPTA1 (αSpI) and SPTAN1 (αSpII) displayed in Figure 4 are extremely informative. 1st order are those proteins that interact directly with the spectrin isoform. 2nd order interactions are proteins that interact with the 1st order set of interacting proteins. Some of the major points are: [1] both erythroid and nonerythroid α spectrins can bind all five β spectrin gene products, but cannot associate with each other. As mentioned above, while the primary form of spectrin tetramers are formed from either α and β erythroid or α and β nonerythroid subunits, Goodman’s laboratory demonstrated that hybrid forms are also present in neurons.⁵⁰ [2] The β-spectrin isoforms cannot associate with each other, but can self-associate. [3] SPTA1 (αSpI) and SPTAN1 (αSpII) associate with different sets of proteins in the nucleus, in the cytoplasm, and proteins in both compartments. Therefore, it is quite likely that all seven spectrin gene products will ultimately be found in both compartments. Many of these localizations have already been demonstrated. [4] The 1st order inner ring α-spectrin isoform interacting proteins are the same, except for the other spectrin isoform (Table 2). This will be discussed further below. [5] The outer ring interactions for SPTA1 (αSpI) and SPTAN1 (αSpII) are different except for the following common interactions: ADD1, CASP3, CDC42, COL4A3, EVL, EZR, F3, FGA, KDM4B, TANK, and UBE21. [4] The 2nd order interactor proteins for SPTA1 (αSpI) and SPTAN1 (αSpII) display very different interactomes. A very prominent difference is the dense protein cloud surrounding polyubiquitin (UBC). Ubiquitin has a well-documented association with SPTA1 (αSpI).^{6–9,88–90} Sangerman et al reported the association of ubiquitin with SPTAN1 (αSpII) in neurons, ^90,91 but this association does not appear in the interactome database. This is an important point. While the spectrinome is very useful, it will become even more so when the protein and interaction databases are more complete. The current human Reactome Pathway database contains approximately 16,000 proteins which represents roughly three quarters of the human proteome (see Table 3). As the number of proteins and interactions grow in these databases, the Spectrinome will become increasingly robust. The current reactome database is very accurate, but not 100%. Occasionally it assigns interactions to both α- and β-spectrin subunits when the assignment should be to only one. An example are the ANK interactions which should only be assigned to the β-spectrin isoforms. On rare occasions there is a miss-assignment. An example is synapsin I (SYN1) which associates with SPTBN1, not SPTAN1. The Spectrinome is dependent on the accuracy of the machine learning tools that scan existing literature, the yeast two hybrid accuracy, and the expertise of those curators who review the data. The Spectrinome is currently of enormous value and its coverage and accuracy will improve with advances in machine learning.

The α Spectrinome

This figure demonstrates the first order interactions of SPTA1 (SPTA1 Level 1) and SPTAN1 (SPTAN1 Level 1), and the second order interactions of SPTA1 (SPTA1 Level 2) and SPTAN1 (SPTAN1 Level 2). First order interactions means those proteins that directly interact with these spectrin isoforms. Second order interactions means those proteins that directly interact with the first order interactors. We explained how the spectrinomes are built in the main text. The proteins in the nucleus, cytoplasm, or both, plus spectrins are color coded as indicated in the figure.

Table 2.

Spectrinome 1^st Order Interactions

Inner Ring
GENE SYMBOL	Protein Name	SPTA1	SPTAN1	SPTB	SPTBN1	SPTBN2	SPTBN4	SPTBN5
ACTB	Actin Beta
ACTR10	Actin-related protein 10
ACTR1A	Alpha-centractin
ANK1	Ankyrin-1
ANK2	Ankyrin-2
ANK3	Ankyrin-3
ARCN1	Coatomer subunit delta
ARF4	ADP-ribosylation factor 4
ARFGAP1	ADP-ribosylation factor GTPase-activating protein 1
ARFGAP2	ADP-ribosylation factor GTPase-activating protein 2
ARFGAP3	ADP-ribosylation factor GTPase-activating protein 3
BET1	Protein transport protein BET1
BET1L	BET1-like protein
CAPZA1	F-actin-capping protein subunit alpha-1
CAPZA2	F-actin-capping protein subunit alpha-2
CAPZA3	F-actin-capping protein subunit alpha-3
CAPZB	F-actin-capping protein subunit beta
CD55	Complement decay-accelerating factor
CD59	CD59 glycoprotein
COG1	Conserved oligomeric Golgi complex subunit 1
COG2	Conserved oligomeric Golgi complex subunit 2
COG3	Conserved oligomeric Golgi complex subunit 3
COG4	Conserved oligomeric Golgi complex subunit 4
COG5	Conserved oligomeric Golgi complex subunit 5
COG6	Conserved oligomeric Golgi complex subunit 6
COG7	Conserved oligomeric Golgi complex subunit 7
COG8	Conserved oligomeric Golgi complex subunit 8
COPA	Coatomer subunit alpha
COPB1	Coatomer subunit beta
COPB2	COPB2
COPE	Coatomer subunit epsilon
COPG1	Coatomer subunit gamma-1
COPG2	Coatomer subunit gamma-2
COPZ1	Coatomer subunit zeta-2
COPZ2	Coatomer subunit zeta-2
DCTN1	Dynactin subunit 1
DCTN2	Dynactin subunit 2
DCTN3	Dynactin subunit 3
DCTN4	Dynactin subunit 4
DCTN5	Dynactin subunit 5
DCTN6	Dynactin subunit 6
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1
DYNC1I1	Cytoplasmic dynein 1 intermediate chain 1
DYNC1I2	Cytoplasmic dynein 1 intermediate chain 2
DYNC1LI1	Cytoplasmic dynein 1 light intermediate chain 1
DYNC1LI2	Cytoplasmic dynein 1 light intermediate chain 2
DYNLL1	Dynein light chain 1, cytoplasmic
DYNLL2	Dynein light chain 2, cytoplasmic
EPB41	Erythrocyte Membrane Protein Band 4.1
FOLR1	Folate receptor alpha
FYN	Tyrosine-protein kinase Fyn
GBF1	Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1
GOLGA2	Golgin subfamily A member 2
GOLGB1	Golgin subfamily A member1
GORASP1	Golgi reassembly-stacking protein 1
GOSR1	Golgi SNAP receptor complex member 1
GOSR2	Golgi SNAP receptor complex member 2
GRB2	Growth factor receptor-bound protein 2
HRAS	GTPase HRas
INS	Insulin
KCNQ2	Potassium voltage-gated channel subfamily KQT member 2
KCNQ3	Potassium voltage-gated channel subfamily KQT member 3
KDELR1	ER lumen protein-retaining receptor 1
KIRREL1	Kin of IRRE-like protein 1
KRAS	GTPase KRas
L1CAM	Neural cell adhesion molecule L1
NCAM1	Neural cell adhesion molecule 1
NFASC	Neurofascin
NPHS1	Nephrin
NRAS	GTPase NRas
NRCAM	Neuronal cell adhesion molecule
PTK2	Protein tyrosine kinase 2
PTPRA	Receptor-type tyrosine-protein phosphatase-like N
RAB1B	Ras-related protein Rab-1B
SCN1B	Sodium channel subunit beta-1
SCN2A	Sodium Voltage-Gated Channel Alpha Subunit 2
SCN2B	Sodium Voltage-Gated Channel Beta Subunit 2
SCN3B	Sodium Voltage-Gated Channel Beta Subunit 3
SCN4A	Sodium Voltage-Gated Channel Alpha Subunit 4
SCN5A	Sodium channel subunit alpha-5
SCN7A	Sodium Voltage-Gated Channel Alpha Subunit 7
SCN8A	Sodium Voltage-Gated Channel Alpha Subunit 8
SOS1	Son of sevenless homolog
SPTA1	Spectrin alpha chain, erythrocytic 1
SPTAN1	Spectrin alpha chain, non-erythrocytic 1
SPTB	Spectrin beta chain, erythrocytic
SPTBN1	Spectrin beta chain, non-erythrocytic 1
SPTBN2	Spectrin beta chain, non-erythrocytic 2
SPTBN4	Spectrin beta chain, non-erythrocytic 4
SPTBN5	Spectrin beta chain, non-erythrocytic 5
SRC	SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase
STX5	Syntaxin-5
TMED10	Transmembrane emp24 domain-containing protein 10
TMED2	Transmembrane emp24 domain-containing protein 2
TMED3	Transmembrane emp24 domain-containing protein 3
TMED7	Transmembrane emp24 domain-containing protein 7
TMED9	Transmembrane emp24 domain-containing protein 9
TMEM115	Transmembrane protein 115
USO1	General vesicular transport factor p115
YKT6	Synaptobrevin homolog YKT6
YWHAB	14-3-3 protein beta/alpha
YWHAE	14-3-3 protein epsilon
Outer Rings
GENE SYMBOL	Protein Name
ACKR1	Atypical Chemokine Receptor 1
ACTA1	Actin, Alpha 1, Skeletal Muscle
ACTN1	Alpha-actinin-1
ACTN2	Actinin Alpha 2
ACTN3	Alpha-actinin-3
ACTN4	Actinin Alpha 4
ACTR1B	Beta-centractin
ADCK3	ArF Domain-Containing Protein Kinase 3
ADD1	Adducin 1
ALAS2	5'-Aminolevulinate Synthase 2
ARF1	ADP Ribosylation Factor 1
ARFGEF1	ADP Ribosylation Factor Guanine Nucleotide Exchange Factor 1
ARHGEF11	Rho Guanine Nucleotide Exchange Factor 11
ATP1B1	Sodium/potassium-transporting ATPase subunit beta-1
ATP1B2	Sodium/potassium-transporting ATPase subunit beta-2
ATP1B3	Sodium/potassium-transporting ATPase subunit beta-3
AZIN1	Antizyme Inhibitor 1
BUB1B	Mitotic checkpoint serine/threonine-protein kinase BUB1 beta
CACNA1C	Voltage-dependent L-type calcium channel subunit alpha-1C
CAPN1	Calpain-1 catalytic subunit
CAPNS1	Calpain Small Subunit 1
CASP3	Caspase-3
CASP7	Caspase 7
CCNT1	Cyclin-T1
CD151	CD151 antigen
CDC42	Cdc42 homolog
CENPE	Centromere-associated protein E
CNTNAP1	Contactin Associated Protein 1
COL17A1	Collagen alpha-1(XVII) chain
COL1A1	Collagen alpha-1(I) chain
COL1A2	Collagen alpha-2(I) chain
COL4A3	Collagen alpha-3(IV) chain
CSF2RB	Cytokine receptor common subunit beta
DBNL	Drebrin Like
DES	Desmin
DMTN	Dematin Actin Binding Protein
DOCK2	Dedicator Of Cytokinesis 2
EGLN2	Egl-9 Family Hypoxia Inducible Factor 2
EHMT2	Euchromatic Histone Lysine Methyltransferase 2
ENAH	ENAH, Actin Regulator
EPB41L1	Erythrocyte Membrane Protein Band 4.1 Like 1
EPB41L2	Erythrocyte Membrane Protein Band 4.1 Like 2
EPB41L3	Erythrocyte Membrane Protein Band 4.1 Like 3
EPB42	Erythrocyte Membrane Protein Band 4.2
EPOR	Erythropoietin Receptor
EVL	Ena/VASP-like protein
EZR	Ezrin
F3	Coagulation Factor III, Tissue Factor
FANCG	Fanconi Anemia Group G Protein
FBLIM1	Filamin Binding LIM Protein 1
FGA	Fibrinogen alpha chain
FLNA	Filamin A
FN3K	Fructosamine 3 Kinase
GATA1	GATA Binding Protein 1
GDF1	Embryonic growth/differentiation factor 1
GLRX5	Glutaredoxin 5
GMDS	GDP-mannose 4,6 dehydratase
GRID2	Glutamate Ionotropic Receptor Delta Type Subunit 2
GRIN1	Glutamate receptor ionotropic, NMDA 1
GRIN2B	Glutamate receptor ionotropic, NMDA 2B
GYPA	Glycophorin A
HBB	Hemoglobin Subunit Beta
HBQ1	Hemoglobin Subunit Theta 1
HEL-S-105	Epididymis secretory protein Li 105
HES1	Hes Family BHLH Transcription Factor 1
HLA-DMA	Major Histocompatibility Complex, Class II, DM Alpha
HLA-DMB	Major Histocompatibility Complex, Class II, DM Beta
HLA-DOA	Major Histocompatibility Complex, Class II, DO Alpha
HLA-DOB	Growth factor receptor-bound protein 2
HLA-DPA1	HLA class II histocompatibility antigen, DP alpha 1 chain
HLA-DPB1	HLA class II histocompatibility antigen, DP beta 1 chain
HLA-DQA1	HLA class II histocompatibility antigen, DQ alpha 1 chain
HLA-DQA2	HLA class II histocompatibility antigen, DQ alpha 2 chain
HLA-DQB1	HLA class II histocompatibility antigen, DQ beta 1 chain
HLA-DQB2	HLA class II histocompatibility antigen, DQ beta 2 chain
HLA-DRA	HLA class II histocompatibility antigen, DR alpha chain
HLA-DRB1	HLA class II histocompatibility antigen, DR beta 1 chain
HLA-DRB3	HLA class II histocompatibility antigen, DR beta 3 chain
HLA-DRB4	HLA class II histocompatibility antigen, DR beta 4 chain
HLA-DRB5	HLA class II histocompatibility antigen, DR beta 5 chain
ITGA1	Integrin Subunit Alpha 1
ITGA6	Integrin alpha-6
ITGB1	Integrin beta-1
ITGB4	Integrin beta-4
JAK2	Tyrosine-protein kinase JAK2
JUP	Junction Plakoglobin
KDM4B	Lysine-specific demethylase 4B
KEL	Kell Metallo-Endopeptidase
KIF11	Kinesin-like protein KIF11
KIF15	Kinesin-like protein KIF15
KIF18A	Kinesin-like protein KIF18A
KIF20A	Kinesin Family Member 20A
KIF22	Kinesin-like protein KIF22
KIF23	Kinesin-like protein KIF23
KIF26A	Kinesin-like protein KIF26A
KIF2A	Kinesin-like protein KIF2A
KIF2B	Kinesin-like protein KIF2B
KIF2C	Kinesin-like protein KIF2B
KIF3A	Kinesin-like protein KIF3A
KIF3B	Kinesin-like protein KIF3B
KIF3C	Chromosome-associated kinesin KIF4A
KIF4A	Kinesin-like protein KIF4A
KIF4B	Chromosome-associated kinesin KIF4B
KIF5A	Kinesin heavy chain isoform 5A
KIF5B	Kinesin Family Member 5B
KIFAP3	Kinesin-associated protein 3
KLC1	Kinesin light chain 1
KLC2	Kinesin light chain 2
KLC3	Kinesin Light Chain 3
KLC4	Kinesin Light Chain 4
KLF1	Kruppel Like Factor 1
KPNB1	Karyopherin Subunit Beta 1
LMNB1	Lamin B1
MAP3K3	Mitogen-activated protein kinase kinase kinase 3
MAPK6	Mitogen-activated protein kinase 6
MAPK8	Mitogen-Activated Protein Kinase 8
MAPRE1	Microtubule Associated Protein RP/EB Family Member 1
MAPRE3	Microtubule Associated Protein RP/EB Family Member 3
MSN	Moesin
MYH9	Myosin Heavy Chain 9
MYL6	Myosin Light Chain 6
NCK1	Cytoplasmic protein NCK1
NFKB1	Nuclear Factor Kappa B Subunit 1
NODAL	Nodal homolog
OSBPL1A	Oxysterol-binding protein-related protein 1
PECAM1	Platelet endothelial cell adhesion molecule
PLEC	Plectin
PPP3CB	Serine/threonine-protein phosphatase 2B catalytic subunit beta isoform
PRKCB	Protein Kinase C Beta
PTPN6	Protein Tyrosine Phosphatase, Non-Receptor Type 6
PXN	Paxillin
RAB7A	Ras-related protein Rab-7a
RAC1	Ras-related protein Rac1
RACGAP1	Rac GTPase-activating protein 1
RB1	Retinoblastoma-associated protein
RHAG	Rh Associated Glycoprotein
RHOA	Transforming protein RhoA
RILP	Rab-interacting lysosomal protein
SCN10A	Sodium Voltage-Gated Channel Alpha Subunit 10
SELENBP1	Selenium Binding Protein 1
SLC4A1	Solute Carrier Family 4 Member 1
SMAD1	Mothers against decapentaplegic homolog 1
SMAD2	SMAD Family Member 2
SMAD3	Mothers against decapentaplegic homolog 3
SMAD4	SMAD Family Member 4
SMAD6	Mothers against decapentaplegic homolog 6
SMAD7	Mothers against decapentaplegic homolog 7
SMAD9	Mothers against decapentaplegic homolog 9
SMURF1	E3 ubiquitin-protein ligase SMURF1
SMURF2	E3 ubiquitin-protein ligase SMURF2
SYN1	Synapsin I
TAL1	T-cell acute lymphocytic leukemia protein 1
TANK	TRAF family member-associated NF-kappa-B activator
TEC	Tyrosine-protein kinase Tec
TFRC	Transferrin Receptor
TGFB1	Transforming Growth Factor Beta 1
TGFB3	Transforming Growth Factor Beta 3
TGFBR1	TGF-beta receptor type-1
TGFBR2	TGF-beta receptor type-2
TIMP2	TIMP Metallopeptidase Inhibitor 2
TJP2	Tight junction protein ZO-2
TLN1	Talin 1
TYR	Tyrosinase
UBC	Ubiquitin-conjugating enzyme E2
UBE2I	SUMO-conjugating enzyme UBC9
VAMP7	Vesicle associated membrane protein 7
VCL	Vinculin
VIM	Vimentin
WNT10B	Wnt Family Member 10B

Open in a new tab

Gray box indicates interaction

Table 3.

Protein Nodes and Interactions

	Level	Reactions	Proteins		Level	Reactions	Proteins
All Spectrin Isoforms				SPTBN1
	1	874	273		1	117	118
	2	29167	6120		2	15179	3397
	3	237999	15123		3	206820	12356
	4	275368	16398		4	272582	13504
SPTA1				SPTBN2
	1	137	136		1	144	145
	2	19342	4989		2	17797	3419
	3	229745	12820		3	195162	12379
	4	272815	13562		4	274737	13579
SPTAN1				SPTBN4
	1	182	183		1	95	94
	2	20880	4335		2	13345	2813
	3	222776	12676		3	184728	12087
	4	272904	13537		4	272022	13485
SPTB				SPTBN5
	1	104	105		1	95	94
	2	13710	2981		2	13424	2822
	3	185775	12173		3	185028	12088
	4	273958	13583		4	272052	13477

Open in a new tab

Figure 5 contains the 1st order interactomes for five β spectrin gene products. The five beta spectrin genes SPTB, SPTBN1, 2, 4, and 5 encode the erythroid (βSpI) and nonerythroid (βSpII, III, IV, and V) spectrin isoforms. The major points observed are: [1] all five beta gene products associate with both SPTA1 (αSpI) and SPTAN1 (αSpII). [2] The interacting proteins for each beta are found in the nucleus, cytoplasm and both compartments. As spoken of above this indicates that all five are likely to be found in both compartments. [3] Many of the 1st order interacting proteins for the five beta spectrins are in common, but the following are not: the β-spectrin isoforms cannot associate with each other, and all do not bind with YWHAB and YWHAE. [4] The outer ring β-Spectrin isoforms interactions are unique except for ARHGEF11 (Table 2).

The β Spectrinome

This figure demonstrates the separate first order spectrinomes for all five spectrin isoforms (SPTB, SPTBN1, SPTBN2, SPTBN4, and SPTBN5).

The complete 1st order Spectrinome was created by linking the two α spectrin and five β spectrin interactomes together. A remarkable visual picture emerges as shown in Figure 6. We provide a list of first order binding partners for all seven individual spectrin gene products in Supplemental Lists 1 to 7.

The Entire First Order Spectrinome

This figure represents the combined first order spectrinomes for all seven spectrin isoform subunits (SPTA1, SPTAN1, SPTB, SPTBN1, SPTBN2, SPTBN4, and SPTBN5). The inner ring proteins have, for the most part, common interactions with the spectrin isoforms, while the outer rings contain unique interactions. All of the proteins in the inner and outer rings are listed in Table 2.

The 273 proteins in the 1st order Spectrinome fall into a large number of pathways that are presented for each spectrin gene product in Table 4. These pathways are involved in [1] functions within the cytoplasm (including all membrane surfaces facing the cytosol), [2] essential nuclear functions, [3] signaling from the cell surface to within the nucleus, and [4] extracellular cell – cell interactions. Given the number of pathways in Table 4 a comprehensive discussion of every pathway is beyond the scope of this minireview. In the coming sections we will give several examples for each of the four categories above.

Table 4:

Spectrin Isoform Pathway Analysis

SPTA1	SPTAN1	SPTB	SPTBN1	SPTBN2	SPTBN4	SPTBN5	Common Pathways
actin binding	actin binding	actin binding	actin binding	actin binding	actin binding	actin binding	actin binding
actin filament binding	actin filament capping	actin filament binding	actin filament capping	actin filament capping	actin filament capping	actin cytoskeleton organization	actin filament capping
actin filament capping	ankyrin binding	actin filament capping	ankyrin binding	adult behavior	adult walking behavior	actin filament capping	ankyrin binding
actin filament organization	Apoptosis	ankyrin binding	ankyrin binding	ankyrin binding	ankyrin binding	ankyrin binding	axon guidance
ankyrin binding	Apoptotic Cleavage of Cellular Proteins	ankyrin binding	axon guidance	antigen processing and presentation of exogenous peptide antigen via MHC class II	axon guidance	axon guidance	DAP12 interactions
axon guidance	Apoptotic Execution Phase	Apaptive Immune System	cadherin binding	Apaptive Immune System	axonogenesis	DAP12 interactions	DAP12 signaling
calcium ion binding	axon guidance	axon guidance	calmodulin binding	axon guidance	cardiac conduction	DAP12 signaling	Developmental Biology
DAP12 interactions	cadherin binding	Cell Cell Communication	Cell Cell Communication	cadherin binding	central nervous system projection neuron axonogenesis	Developmental Biology	endoplasmic reticulum to Golgi vesicle-mediated transport
DAP12 signaling	calcium ion binding	DAP12 interactions	common-partner SMAD protein phosphorylation	cerebellar Purkinje cell layer morphogenesis	clustering of voltage-gated sodium channels	dynactin binding	Fc epsilon receptor (FCERI) signaling
Developmental Biology	calmodulin binding	DAP12 signaling	DAP12 interactions	DAP12 interactions	cytoskeletal anchoring at plasma membrane	dynein intermediate chain binding	FCERI mediated MAPK activation
endoplasmic reticulum to Golgi vesicle-mediated transport	Caspase Mediated Cleavage of Cytoskeletal Proteins	Developmental Biology	DAP12 signaling	DAP12 signaling	DAP12 interactions	endoplasmic reticulum to Golgi vesicle-mediated transport	Innate Immune System
Fc epsilon receptor (FCERI) signaling	Caspase Pathway	endoplasmic reticulum to Golgi vesicle-mediated transport	Developmental Biology	Developmental Biology	DAP12 signaling	Fc epsilon receptor (FCERI) signaling	Insulin receptor signalling cascade
FCERI mediated MAPK activation	Cell Cell Communication	Fc epsilon receptor (FCERI) signaling	endoplasmic reticulum to Golgi vesicle-mediated transport	endoplasmic reticulum to Golgi vesicle-mediated transport	Developmental Biology	FCERI mediated MAPK activation	Interaction Between L1 and Ankytins
Heme Metabolism	DAP12 interactions	FCERI mediated MAPK activation	Fc epsilon receptor (FCERI) signaling	Fc epsilon receptor (FCERI) signaling	endoplasmic reticulum to Golgi vesicle-mediated transport	Golgi organization	Interleukin receptor SHC signaling
hemopoiesis	DAP12 signaling	Heme Metabolism	FCERI mediated MAPK activation	FCERI mediated MAPK activation	Fc epsilon receptor (FCERI) signaling	Innate Immune System	Interleukin-2 signaling
Innate Immune System	Death Pathway	Immune System	Golgi to plasma membrane protein transport	Immune System	FCERI mediated MAPK activation	Insulin receptor signalling cascade	Interleukin-3, 5 and GM-CSF signaling
Insulin receptor signalling cascade	Developmental Biology	Innate Immune System	GTPase binding	Innate Immune System	fertilization	Interaction Between L1 and Ankytins	IRS-mediated signalling
Interaction Between L1 and Ankytins	endoplasmic reticulum to Golgi vesicle-mediated transport	Insulin receptor signalling cascade	Innate Immune System	Insulin receptor signalling cascade	Innate Immune System	Interleukin receptor SHC signaling	L1CAM Interatctions
Interleukin receptor SHC signaling	FAS Pathway	Interaction Between L1 and Ankytins	Insulin receptor signalling cascade	Interaction Between L1 and Ankytins	Insulin receptor signalling cascade	Interleukin-2 signaling	MAPK cascade
Interleukin-2 signaling	Fc epsilon receptor (FCERI) signaling	Interleukin receptor SHC signaling	Interaction Between L1 and Ankytins	Interleukin receptor SHC signaling	Interaction Between L1 and Ankytins	Interleukin-3, 5 and GM-CSF signaling	Ncam Signaling for Neurite Out Growth
Interleukin-3, 5 and GM-CSF signaling	FCERI mediated MAPK activation	Interleukin-2 signaling	Interleukin receptor SHC signaling	Interleukin-2 signaling	Interleukin receptor SHC signaling	IRS-mediated signalling	phospholipid binding
IRS-mediated signalling	HIVNEF Pathway	Interleukin-3, 5 and GM-CSF signaling	Interleukin-2 signaling	Interleukin-3, 5 and GM-CSF signaling	Interleukin-2 signaling	kinesin binding	RAF/MAP kinase cascade
L1CAM Interatctions	Innate Immune System	IRS-mediated signalling	Interleukin-3, 5 and GM-CSF signaling	IRS-mediated signalling	Interleukin-3, 5 and GM-CSF signaling	L1CAM Interatctions	Ras guanyl-nucleotide exchange factor activity
lymphocyte homeostasis	Insulin receptor signalling cascade	KRAS Signaling	IRS-mediated signalling	KRAS Signaling	IRS-mediated signalling	lysosomal transport	Signal Transduction
MAPK cascade	Interaction Between L1 and Ankytins	L1CAM Interatctions	L1CAM Interatctions	L1CAM Interatctions	L1CAM Interatctions	MAPK cascade	Signaling by Insulin receptor
Ncam Signaling for Neurite Out Growth	Interleukin receptor SHC signaling	MAPK cascade	MAPK cascade	MAPK cascade	MAPK cascade	myosin tail binding	Signaling by Interleukins
phospholipid binding	Interleukin-2 signaling	MHC Class II Antigen Presentation	membrane assembly	MHC Class II Antigen Presentation	Ncam Signaling for Neurite Out Growth	Ncam Signaling for Neurite Out Growth	Signaling by VEGF
plasma membrane organization	Interleukin-3, 5 and GM-CSF signaling	Mitotic Spindle	mitotic cytokinesis	multicellular organism growth	negative regulation of heart rate	phospholipid binding	SOS-mediated signalling
porphyrin-containing compound biosynthetic process	IRS-mediated signalling	Ncam Signaling for Neurite Out Growth	Mitotic Spindle	Ncam Signaling for Neurite Out Growth	phosphatase binding	protein homooligomerization	structural constituent of cytoskeleton
positive regulation of protein binding	L1CAM Interatctions	Nephrin Interactions	Ncam Signaling for Neurite Out Growth	phospholipid binding	phospholipid binding	protein self-association	VEGFA-VEGFR2 Pathway
positive regulation of T cell proliferation	MAPK cascade	phospholipid binding	Nephrin Interactions	postsynapse organization	positive regulation of multicellular organism growth	RAF/MAP kinase cascade	VEGFR2 mediated cell proliferation
protein heterodimerization activity	Mitotic Spindle	RAF/MAP kinase cascade	phospholipid binding	RAF/MAP kinase cascade	protein localization to plasma membrane	Ras guanyl-nucleotide exchange factor activity
RAF/MAP kinase cascade	Myogenesis	Ras guanyl-nucleotide exchange factor activity	plasma membrane organization	Ras guanyl-nucleotide exchange factor activity	RAF/MAP kinase cascade	Signal Transduction
Ras guanyl-nucleotide exchange factor activity	Ncam Signaling for Neurite Out Growth	Signal Transduction	positive regulation of interleukin-2 secretion	Signal Transduction	Ras guanyl-nucleotide exchange factor activity	Signaling by Insulin receptor
regulation of cell shape	Nephrin Interactions	Signaling by Insulin receptor	positive regulation of protein localization to plasma membrane	Signaling by Insulin receptor	regulation of peptidyl-serine phosphorylation	Signaling by Interleukins
Signal Transduction	neutrophil degranulation	Signaling by Interleukins	protein localization to plasma membrane	Signaling by Interleukins	regulation of sodium ion transport	Signaling by VEGF
Signaling by Insulin receptor	phospholipid binding	Signaling by VEGF	protein-containing complex binding	Signaling by VEGF	sensory perception of sound	SOS-mediated signalling
Signaling by Interleukins	RAF/MAP kinase cascade	SOS-mediated signalling	RAF/MAP kinase cascade	SOS-mediated signalling	Signal Transduction	spectrin binding
Signaling by VEGF	Ras guanyl-nucleotide exchange factor activity	structural constituent of cytoskeleton	Ras guanyl-nucleotide exchange factor activity	structural constituent of cytoskeleton	Signaling by Insulin receptor	structural constituent of cytoskeleton
SOS-mediated signalling	Signal Transduction	TGF_BETA Signaling	regulation of protein localization to plasma membrane	structural constituent of synapse	Signaling by Interleukins	VEGFA-VEGFR2 Pathway
structural constituent of cytoskeleton	Signaling by Insulin receptor	TGFBR Pathway	regulation of SMAD protein signal transduction	synapse assembly	Signaling by VEGF	VEGFR2 mediated cell proliferation
VEGFA-VEGFR2 Pathway	Signaling by Interleukins	VEGFA-VEGFR2 Pathway	RNA binding	VEGFA-VEGFR2 Pathway	SOS-mediated signalling
VEGFR2 mediated cell proliferation	Signaling by VEGF	VEGFR2 mediated cell proliferation	Signal Transduction	VEGFR2 mediated cell proliferation	spectrin binding
	SOS-mediated signalling		Signaling by Insulin receptor	vesicle-mediated transport	structural constituent of cytoskeleton
	structural constituent of cytoskeleton		Signaling by Interleukins		transmission of nerve impulse
	TNFR1 Pathway		Signaling by VEGF		VEGFA-VEGFR2 Pathway
	UCALPAIN Pathway		SOS-mediated signalling		VEGFR2 mediated cell proliferation
	VEGFA-VEGFR2 Pathway		structural constituent of cytoskeleton		vesicle-mediated transport
	VEGFR2 mediated cell proliferation		TGF_BETA Signaling
			TGFBR Pathway
			VEGFA-VEGFR2 Pathway
			VEGFR2 mediated cell proliferation

Open in a new tab

Functions within the Cytoplasm including Cytosol Facing Membrane Surfaces

Just as there are multiple spectrin gene products the same is true for ankyrin, and protein 4.1. Nonerythroid ankyrin was first described by Bennett and Davis,⁹³ and we now know that there are three distinct ANK genes and proteins: ANK1 or Ankyrin R (human chromosome 8); ANK2 or Ankyrin B (human chromosome 4); and ANK3 or Ankyrin G (human chromosome 10).⁹⁴ Goodman and colleagues described a protein 4.1 analogue in brain, that had an apparent molecular weight of 87 kDa, and localized in the identical pattern as the erythroid form of spectrin in mouse cerebellum.⁹⁵ It was demonstrated to bind to Spectrin, be distinct from Synapsin I, and was given the name Amelin,⁹⁶ but we now refer to this form as 4.1R. Zimmer et al found a form of Amelin (protein 4.1) that localized to axons in mouse cerebellum.⁹⁷ Much like the spectrin story we realized that there were both erythroid and nonerythroid 4.1 isoforms, which co-localized with the erythroid and non-erythroid spectrin isoforms in neurons.⁹⁸ Today we know there are four 4.1 isoforms: 4.1R (EPB41), 4.1N (EPB41L1), 4.1G (EPB41L2) and 4.1B (EPB41L3).⁹⁹ The 4.1 isoforms interact with many important transmembrane proteins. One example is the store-operated Ca²⁺ channel in endothelial cells.^100–102

ANK1, 2 and 3⁹⁴ and 4.1 R, G and N⁹⁹ can each bind to a wide range of transmembrane proteins, and these associations are essential for many functions including the ion channels, transporters and several enzymes and these interactions and functions have been well chronicled. In this review, we will focus on the direct interactions of spectrin with other proteins and the functional pathways that are influenced by these interactions.

All forms of ankyrin bind to each β spectrin isoform in the β15 repeat between residues 1776 and 1898.^103–105 All forms of protein 4.1 bind to each β spectrin isoform in the CH2 domain between residues 171 and 282.¹⁰⁶ Heme binds to βSpII in the β11-12 region between residues 1450 and 1494.⁶⁴ The Synapsin I/II binding domain within βSpII has been assigned to a very specific CH2 domain region of residue 211-235.¹⁰⁷ Important to this discussion is that fact the protein 4.1 can compete with Synapsin I and II for binding to intact βSpII.¹⁰⁸ The importance of this spectrin- synapsin interaction to synaptic transmission is described below.

The best-known cytoplasmic function of spectrin comes from our knowledge of the erythrocyte membrane skeleton, which provides membrane stability, shape, flexibility and elasticity.^109–111 This raises the question of whether there are similar structures as the spectrin membrane skeleton on the cytoplasmic surface of organelle membranes and, if so, does it play similar functions described above? We know that each of the organelle membrane cytoplasmic components contain isoforms of spectrin, ankyrin and protein 4.1.^{2,4,9,25,92,94,99} But can they assemble into structures similar to the erythrocyte membrane skeleton and confer similar properties? The answer is yes. In neurons spectrin, actin, adducin, and associated proteins (4.1 and ankyrin) form what has been referred to as membrane associated periodic skeleton (MPS), observed using the super resolution stochastic optical reconstruction microscopy (STORM) methodology. MPS are rings around the cytoplasmic surface of axons, with the rings connected by spectrin tetramers that provide a 190nm periodicity¹¹². The MPS is thought to supply structure, flexibility and mechanical support to axons. MPS also controls the lateral mobility of transmembrane proteins defining which proteins are confined to different axonal segments, and provides stability to axonal microtubules. In more recent studies, MPS have also been found in dendrites. Of substantial interest, Han et al¹¹³ demonstrated a 2D polygonal lattice that reminded the authors of the erythrocyte membrane skeleton in the somato-dendritic compartment of cultured hippocampal neurons using antibodies against βSpII and βSpIII and the STORM methodology. The authors conclude “Taken together, these results suggest a membrane skeleton with a 2D polygonal lattice structure is formed in the somatodendritic compartment of neurons”. This was a clear demonstration of an erythrocyte membrane skeleton-like structure in neurons, and demonstrates that different compartments of neurons can contain this structure (somato-dendrite) or MPS rings (axons and some dendrites). What would be very interesting would be for this study to be performed with βSpI and/or αSpI antibodies, which should recognize the major isoform of spectrin in soma and dendrites of hippocampal neurons (αSpI/βSpIΣ2). As diverse nonerythroid cells and their organelles carry out different functions it is not at all surprising that the spectrin membrane skeleton will take on different structures required for specific functional needs.

Inspection of the spectrinome demonstrates a large number of cytoplasmic proteins involved in membrane traffic. Spectrin isoforms are involved in both anterograde and retrograde transport along microtubules, utilizing kinesin family motors and cytoplasmic dynein motors respectively. The earliest example that spectrin was involved in anterograde transport occurred before fodrin was known to be a non-erythroid spectrin isoform (now called αSpII/βSpII or αSpII /βSpIII). Levine and Willard found a protein with subunits of 250kDa and 240kDa apparent molecular weight in the cortical cytoplasm of neuronal and non-neuronal tissues.⁴⁷ Because they felt that this protein looked like a lining of the cell they named it based on the Greek word fodros, meaning lining, fodrin. They had previously found that these two proteins, originally called 26 and 27, travelled the axon from the soma of retinal ganglion neurons to the presynaptic terminal at two speeds: 40 mm/day along with mitochondria and other membranous vesicles, and at slower velocities along with actin, myosin, neurofilament and microtubule proteins. Levine and Willard noticed that the apparent molecular weights of 250 and 240 kDa was similar to those found for filamin and spectrin, so they tried to show a relationship using their fodrin antibody. Unfortunately, they were using a rather insensitive Ouchterlony immunodiffusion technique, where you looked for a precipitin line between the antibody well and the antigen wells. While they clearly observed such a precipitin line with fodrin, they observed no precipitin line with filamin or spectrin. It is historically interesting why they missed that they were studying non-erythroid spectrin, but does not at all diminish the importance of this study. Levine and Willard had demonstrated for the first time that what we now know as non-erythroid spectrin is intimately involved in anterograde rapid and slow transport down the axon.⁴⁷ Today we know that the slow transport is actually not slow at all, but instead involves multiple stops and starts along the microtubule pathway.

A quick look at the Spectrinome indicates SPTBN2 (or βSpIII) association with a large number of kinesin superfamily members, referred to as KIFs: KIF 11, 15, 18A, 20A, 22, 23, 26A, 2A, B, C, 3A, B, C, 4A, B, 5A, 5B, AP3. These Kinesin superfamily proteins use the energy of ATP hydrolysis to move cargo along microtubules, most (the N-Kinesins) in the plus-end directed anterograde transport. Different cargos utilize distinct Kinesin Superfamily members (those in bold are associated with βSpIII): synaptic vesicle precursors (transported by KIF5 motors and KIF1A or KIF1Bβ), plasma membrane precursors (KIF5 motors and KIF3), mitochondria (KIF1Bα and KIF5 motors), lysosomes (KIF5 motors), N-cadherin or β-catenin containing vesicles (KIF3), and mRNAs (KIF5).¹¹⁴ I will provide one exemplar. Takeda et al¹¹⁵ showed that antibody FAB fragments directed against KIF3B blocked fast axonal transport of vesicles, when microinjected into superior cervical ganglion neurons in culture, and inhibited neurite extension. Further they demonstrated by a yeast two hybrid binding assay, co-immunoprecipitation from a rat cauda equina vesicle preparation, immuno-electron-microscopy, and similar rates of axonal transport that KIF3 associated directly with fodrin (from what we know from the Spectrinome this association is with βSpIII), and therefore αSpII/βSpIII is serving as the scaffold which directly attaches the KIP3 motor to the vesicle cargo. Given the many KIPs that associate with βSpIII (or SPTBN2), it is quite likely that this spectrin isoform plays the same role for other anterograde translocation of cargo.

We have known for over 30 years that spectrin, ankyrin, and protein 4.1 isoforms can be found on Golgi cisternae where they form an erythrocyte-like two-dimensional skeleton regulating it’s shape and vesicle transport.^5,116 Salcedo-Sicilia et al have demonstrated that βSpIII is enriched in the distal Golgi compartments where it provides structural support and shape and is required for anterograde transport.¹¹⁷ Further they demonstrated that PI4P is required for βSpIII membrane association.

Spectrin also plays an essential role in retrograde movement of cargo, via the ATP dependent motor called cytoplasmic dynein. Cytoplasmic dynein is involved in the retrograde microtubule based axonal transport from the presynaptic terminal to the soma, vesicle trafficking from the Golgi to the ER, and mitotic spindle assembly (discussed later). A look at the Spectrinome inner ring indicates several key proteins essential for these functions: Alpha-centractin or Arp1 (ACTR1A), the Dynactin subunits (Dynactin1-6), and the cytoplasmic Dyneins (DCTN1-6 plus the heavy, intermediate, and light chains subunits). The Spectrinome outer ring proteins include: Beta-centractin (ACTR1B) which associates with SPTBN2 or βSpIII. Cytoplasmic Dynein contained dimerized heavy chains (DYNC1H1) associated with two light intermediate chains (DYNC1LI1 and DYNC1LI2). Dynactin, a 23-subunit complex, associates with Dynein activating the motor. Dynactin contains a 37 nm actin like filament that is referred to as the ARP1 filament. The ARP1 filament is composed of eight Arp1 subunits (ACTR1A), one β-actin, one Arp 11 (ACTR10), which interacts with p25, 27, and 62 (DCTN 5, 6 and 4) to form the pointed minus end of dynactin. CapZa and CapZb cap the barbed end, while two p24 (DCTN3) subunits and four p50 (DCTN2) subunits and two p150^Glued (DCTN1) bind to the pointed end. There are several activator and adaptor proteins that are beyond the scope of this discussion.¹¹⁸ Again, we would like to give one exemplar of spectrin function related to retrograde transport of vesicle within the cell cytoplasm. Holleran et al demonstrated that βSpIII interacts with Arp1 directly and that brings the Dynactin complex and Dynein motor to associate with the spectrin associated cargo.¹¹⁹ They demonstrate that in neurons this is involved in retrograde vesicular traffic, while in interphase cells the βSpIII and dynactin colocalize with vesicles in the perinuclear region of the cytoplasm, and the developing cleavage furrow and mitotic spindle of dividing cells.¹¹⁹

To complete this section, we will describe the association of spectrin (αSpII/βSpII) with synaptic vesicles and the essential role that this plays in synaptic transmission. Goodman and colleagues over a period of approximately 15 years demonstrated by immunoelectron-microscopy that αSpII/βSpII was associated with small spherical 50 nm synaptic vesicles,⁵ that this interaction of αSpII/βSpII was via synapsin I,¹²⁰ which bound to the tails of the βSpII subunit,¹⁰⁸ and was independent of synapsin phosphorylation.¹²¹ Sikorski et al¹²² demonstrated that a peptide specific antibody, directed against the region of βSpII [A207- V445] predicted by Ma et al⁶⁴ to be the synapsin I binding domain, could block synaptic transmission in paired hippocampal neurons while peptide specific antibodies against closely flanking regions had no significant effect.¹²² Building on these studies, Zimmer et al, by utilizing recombinant peptides demonstrated that the synapsin I binding domain resided within a 25 amino acid stretch of the βSpII CH2 domain (residues 211-235).¹⁰⁷ Further, peptide specific antibody FAB fragments against this 25 amino acid domain rapidly inhibited synaptic transmission in the same paired hippocampal neuron preparation.¹⁰⁷ By this series of studies, recognized as one of the most important contributions to 20th century neuroscience,¹²³ Goodman and colleagues had established an essential role for non-erythroid spectrin (αSpII/βSpII) in synaptic transmission.¹²³ Goodman et al have proposed, in the casting the line hypothesis,⁴⁹ that the interaction of synapsin I (and possibly synapsin II) with spectrin at the active zone cause the dimpling in of the presynaptic membrane towards the vesicle, thus allowing αSpII/βSpII to serve as a scaffold on which the fusogenic v-snares, t-snares and Ca⁺² regulatory proteins can assemble to allow exocytosis of neurotransmitter upon local elevation of Ca⁺².

Essential Nuclear Functions

Last year Muriel Lambert, the Special Editor of this Thematic Issue, published a comprehensive description in this journal covering the functions of spectrin, and its partners in the nucleus.¹²⁴ We refer the reader to this well-crafted EBM review for detailed coverage of this topic, as we will focus on a few examples of spectrin isoform specific function. Historically it is interesting to ask why the study of nuclear spectrin lagged behind the study of cytoplasmic (including membrane) spectrin by more than a decade. We believe that the answer is two-fold. First, the expectations of what spectrin might be doing in non-erythroid cells was influenced by what we knew about the erythrocyte membrane skeleton. But perhaps more importantly the staining of a wide range of cells and tissues by immunofluorescence and immuno-electron microscopy always showed more intense staining in the cytoplasm as compared to the nucleus when using anti-erythroid or anti-nonerythroid spectrin antibodies.^{5,37,42,125–130} This is only of historical interest, as we now know that spectrin isoforms play essential roles in the nucleus.

Lambert and colleagues have demonstrated a critical scaffold function for spectrin in DNA repair.¹²⁴ To repair interstrand cross-links (ICLs), αSpII binds to DNA at the site of ICL damage. FANCG binds to the SH3 domain of αSpII, followed by ERCC1 binding to FANCG. XPF, an endonuclease, then binds to ERCC1 and incises the DNA damage and repair occurs.^{124,131–142} Fanconi Anemia is a bone marrow failure disorder, where there is a deficiency in αSpII leading to diminished DNA ICL repair.¹²⁴ It has been proposed that Fanconi Anemia (FA) proteins, FANCG and FANCA, can bind to the αSpII SH3 domain protecting αSpII from calpain cleavage.¹⁴⁰ Consistent with this concept, there are patient derived mutations in at least one FA gene, FANCG, which result in the FANCG protein having a defect in the motif that binds to the SH3 domain.¹⁴⁰

Telomeres are regions at the end of chromosomes with repetitive nucleotide sequences that protect genomic stability.^144–146 αSpII plays a similar role as described above in serving as a scaffold required for repair of ICL damaged telomeric DNA.^124,147 αSpII localizes to telomeres during S phase, where it stimulates the association of TRF1 and TRF2 required for the binding of XPF, demonstrating an important role in DNA repair at the replication fork.^124,147

The nuclear envelope contains and outer membrane, inner membrane and a perinuclear space. A nuclear pore complex allows the bidirectional movement of molecules through the nuclear envelope, and a LINC (linker of nucleoskeleton and cytoskeleton) complex allows association between the nuclear skeleton and the cytoskeleton. The LINC complex plays a mechano-sensory function that allows the cell to react to modulation of homeostasis within the extracellular, cytoplasmic or nuclear compartments.^148–151 It is composed of several major proteins, including SUN1/2 that forms heterotrimers which are in contact with the nuclear lamina on the nuclear side of the inner membrane, but is also in contact with the Nespirin family KASH (Klarsicht, ANC-1, and Syne homology) domain in the perinuclear space.^151,152 The nespirins are transmembrane proteins that cross the outer nuclear membrane. They contain varied numbers of spectrin repeat units, and some contain actin binding CH domains (Nespirin 1 and 2) and all contain KASH domains. Nespirin 1 and 2 can directly bind to cytoplasmic actin filaments, with or without accessory proteins. The smaller Nespirin 1α2, which lacks an actin binding domain, can associate directly with Kinesin 1 thereby associating the nuclear envelope to cytoplasmic microtubules. Nespirin 3 can associate indirectly to cytoplasmic intermediate filaments via proteins such as plectin (also contains spectrin repeat units).^151–153 Several transmembrane inner nuclear membrane proteins associate with the lamins and/or chromatin. Lamins A/C and B nuclear lamina intermediate filament interact directly with heterochromatin. Heterochromatin also bind to Emerin via HDAC3. The Lamin B receptor associates with lamin B and heterochromatin via HP1 (heterochromatin protein 1). αSpII associates with Lamin B1 and Plectin (Table 2). The nuclear lamina, an intermediate filament structure, made up of lamins A and B has multiple functions including involvement in gene expression and maintenance of chromatin and nuclear structure.^151–159

The nucleoskeleton consist of the nuclear lamina just below the inner nuclear membrane and an interacting spectrin/actin skeleton that also includes myosin and protein 4.1.¹²³ αSpII has been reported to interact with several nucleoskeleton proteins, based on coimmunoprecipitation from HeLa and human lymphoblastoid cells, including βSpIVΣ5, βSpII, actin, protein 4.1, lamin A, emerin and nuclear myosin1c.^160,161 Holaska and Wilson,¹⁶¹ using an recombinant bead-conjugated emerin to pull down emerin complexes from HeLa nuclear extract, observed seven complexed proteins: nuclear αII-spectrin, non-muscle myosin heavy chain alpha, Lmo7 (a predicted transcription regulator), nuclear myosin I, β-actin, calponin 3 and SIKE (suppressor of IKKε- and TBK1-activation of interferon response elements). These authors went on to further immuno-pulldown and binding assays to determine an emerin proteome. Emerin plays multiple roles in the spectrin-actin cortical network including minus end capping of actin filaments, linking centrosomes to the nuclear inner membrane, and regulating β-catenin activity.^157–159 The data taken together from Sridharan et al¹⁶⁰ and Holanska and Wilson¹⁶¹ suggest that these nuclear spectrin complexes include a spectrin/actin skeleton associated with the nuclear lamina, the inner nuclear membrane via emerin, myosin and transcription factors.

Historically, the structure and function of the nuclear lamina was understood well before the discovery of nuclear spectrin.^124,162 As discussed above the nucleoskeleton is an integrated combination of the nuclear lamina and the spectrin-actin network. The nucleoskeleton provides important mechanosensory properties to the nucleus. The spectin-actin lattice provides the properties of elasticity and response to compression, reminiscent of the functions of the erythrocyte membrane skeleton.^163,164 The nuclear lamina provides mechanical stiffness to the nuclear membrane.^165–168 In summary nuclear spectrin is involved in DNA repair, telomere integrity, nuclear architecture, properties of mechanical stability and elasticity of the nuclear envelope, and signaling from the extracellular space into the nucleus. The later will be the subject of the next section.

Signaling From the Cell Surface to Within the Nucleus

The Spectrinome shows the interaction of αSpII with several SMADs (SMAD 1, 6, 7, 9), SMURF 1 and 2; while βSpII interacts with SMAD 2, 3, 4, TGFB1 and B3, TGFBR1 and 2. This clearly demonstrates a central role of non-erythroid spectrin isoforms in the TGF-β signaling pathway. The TGF-β signaling pathway is involved in many functions of normal cells including, but not limited to, pattern formation during embryonic development, ECM production, angiogenesis, tissue repair, immune regulation, cell differentiation, cell growth and proliferation, and apoptosis.¹⁶⁹ For such an impactful set of cellular processes the pathway, as it relates to spectrin is rather simple.^111,170,171 The TGF-β receptor 2 (TGFBR2) is a Ser/Thr receptor kinase. When TGF-β binds to TGFBR2, it results in association and phosphorylation of the TGF-β receptor 1 (TGFBR1). TGFBR1 then recruits and phosphorylates SMAD2 or SMAD3. The phosphorylated SMAD3 dissociates from the receptor and associates with SMAD4 (a known tumor suppressor) and βSpII. The SMAD3/4- βSpII complex enters into the nucleus together and associate with specific transcription factors and a TGF-β-response element in target genes. This in turn leads to increased specific target gene transcription. As an example, if the function is cell cycle regulation then examples of targets are Cyclin dependent kinase inhibitors, which inhibit cyclin D/CDK4/6 activity blocking the cell cycle at the G1 phase; and p21 which mediates the anti-proliferative response and provides a partial explanation for tumor-suppression by the TGF-β signaling pathway. The SMURFS are E3 Ubiquitin ligases which polyubiquitinate the SMADS, leading to their turnover by 26S proteasomes.^111,169–171

As mentioned at the start of this section, αSpII also is associated with several SMADs and SMURF 1 and 2. Metral et al demonstrated that decreasing αSPII in a cell line derived from human melanoma cells resulted in cell cycle arrest at the G1 checkpoint.¹⁷² They further demonstrated that αSpII deficiency led to increased expression of the cyclin-dependent kinase inhibitor: p21^Cip.¹⁷² This suggests that both αSpII and βSpII are involved in cell cycle control via TGF-β/SMAD signaling.

Extracellular Cell – Cell Interactions

Pollerberg et al¹⁷³ demonstrated by fluorescence recovery after photobleaching (FRAP) technology, that NCAM140 moved more rapidly than NCAM180 in the plasma membrane of a neuroblastoma cell line. In this study, NCAM180 was suggested to be restricted in its mobility by interaction with the cytoskeleton, and brain spectrin appeared to copurify with NCAM180 but not NCAM140. In a related article from Pollerberg et al¹⁷⁴, NCAM180, but not NCAM140 or NCAM120, was demonstrated to be concentrated in areas of cell-cell contact in both the neuroblastoma cell line and primary cultures of cerebellar neurons. Further, this study directly tested the association of the NCAMs and brain spectrin. Brain spectrin bound only to NCAM180, via its C-terminal cytoplasmic domain, and it did not bind to NCAM140 or NCAM 120 that lack this domain.¹⁷⁴ This demonstrated a direct association of spectrin with NCAM180.

The NCAMs are members of the Immunoglobulin superfamily adhesion molecules, which also includes the L1 family.¹⁷⁵ The Immunoglobulin superfamily are cell surface transmembrane proteins that have one to five Ig domains and three fibronectin III (FNIII) homologous domains in their extracellular domain. Their extracellular domains are involved in hemophilic and heterophilic interactions with adhesion molecules at sites of cell contact and ion channels respectively. They serve many functions in neurodevelopment, and synaptic functions essential for learning and memory; and interact with various ion channels, neurotransmitter and cytokine receptors.¹⁷⁵ The Spectrinome shows several Immunoglobulin superfamily members in the inner ring, associating with all spectrin isoforms.

For a few examples of the published interactions: NCAM180 binds to αSpI/βSp1Σ2;^174,175 L1 binds via ANK B to αSpII/βSpII; CHL1 associates directly with βSpII or indirectly via ankyrin; Neurofascin binds to αSpII/βSpII via ANK G; and SynCAM 1 associates with αSpII/βSpII via 4.1B.^111,170,175 The association of NCAM180 to αSpI/βSp1S2 recruits spectrin associated-NMDA receptors and CAM Kinase IIa to the spectrin scaffold at post synaptic densities.¹⁷⁶ The NMDA Receptor is an ionotropic glutamate receptor, that is essential for controlling synaptic plasticity and is linked to memory and learning.^175,176 We showed in our immuno-electron microscopy (see Figure 2 for summary) that αSpI/βSpIS2 is highly enriched in post-synaptic densities,⁵ and Sytnyk et al demonstrated that NCAM180 drives both spectrin and CAM Kinase IIα to this post-synaptic complex.¹⁷⁶ In the NCAM-/- mice that they utilized the NMDA receptor–dependent form of long-term potentiation (LTP) was impaired.¹⁷⁶ Therefore defects in this spectrin scaffold could be critical for psychiatric disorders such as bipolar disease and schizophrenia.¹⁷⁵

Why is Spectrin’s Chimeric E2-E3 Activity Important to Spectrin Isoform Functions?

There have been several reviews that describe our discovery that erythroid spectrin is not only an essential scaffold protein serving all the functions described in previous sections of this review, but also has an essential function as an E2/E3 chimeric ubiquitin conjugating and ligating enzyme.^8,9,92 A relatively recent EBM review by Goodman et al⁹, covered the history of this discovery of erythroid spectrin’s E2/E3 activity, but also the very likely probability that αSpII has the very same function with a greater number of target proteins. Therefore, we will cover the history in just enough detail to be able to describe just how important we believe this enzymatic function will be for normal cellular homeostasis and disease states that are accompanied by oxidative stress.

Kakhniashvili et al first demonstrated that human alpha spectrin (αSpΣ1) had an E2 ubiquitin conjugating activity that had the ability to target itself.⁶ We proposed, based on sequence and structural analysis, that cysteine 2071 would be the essential E2 site as it was found within a 17 amino acid sequence that had 70% identity to all known consensus E2 active sites.⁶ We also proposed, based on structural analysis, that cysteine 2100 could play a role in ubiquitin transfer. Both cysteine 2071 and cysteine 2100 are found within αSpI repeat 20 and we predicted that a lysine rich region within repeat 21 could be the target site.⁶ At this time, we did not yet know whether a separate E3 ligating enzyme was required or whether spectrin was capable of ubiquitinating other associated proteins. Over the following four years both questions were answered.

Hsu et al⁷, using a recombinant αSpI GST-protein (2005-2415) which contained the αSp repeats 20 and 21 and reached to the C-terminus of αSpI, demonstrated that this domain of spectrin had the ability to ubiquitinate itself in the presence of purified E1 enzyme and ATP, but in the absence of any E3 ligase. Hsu et al had demonstrated that this predicted fragment did contain a chimeric E2/E3 activity capable of ubiquitinating itself. Further mutating the six cysteines in this protein, either individually or collectively, demonstrated that Cysteine 2071 is the cysteine that can serve as the E2/E3 site.^7,8 Cysteine 2100 serves a backup E2/E3 function in humans only, as this cysteine is converted to a tyrosine or glutamine in other mammalian species.^7–9

Chang et al^70,71,177 demonstrated that spectrin was capable of ubiquitinating not only alpha spectrin, but also ankyrin, band 3, protein 4.1 and a protein of unknown function (gi 13278939). The ability of a site on αSpI repeat 20 to ubiquitinate protein 4.1 could be explained by the proximity to the 4.1 binding domain. However, ubiquitination of ankyrin and band 3 required either: [a] that one spectrin molecule can ubiquitinate sites on an adjacent spectrin molecule, or [b] that the condensation of spectrin down to 55 nm brings the enzymatic site in close proximity to the target protein, or [c] that the ubiquitination of these other proteins requires a separate E3 ubiquitin ligase. Possibility [c] was ruled out as no exogenous E3 was added in these ubiquitination assays.^70,71,177 During the preparation of this review, we searched the existing literature to gain possible insight into the possible role of the unknown protein gi 13278939. What we found holds special interest for this review. Two studies using human embryonic kidney HEK293 cells and either Proliferating Cell Nuclear Antigen (PCNA) affinity resin¹⁷⁸ or PCNA proximity labelling and pull down¹⁷⁹, followed by proteomics and interactomics, have demonstrated an association between gi 13278939 and PCNA. In the case of Ohta et al gi 13278939 was pulled out of a nuclear extract with PCNA resin.¹⁷⁸ PCNA is essential for chromatin establishment and remodeling, DNA replication, DNA repair and sister chromatid cohesion. It functions as a homo-trimer that encircles DNA, tethering DNA polymerases to DNA. Therefore, to summarize, a target of SpI E2/E3 ubiquitin conjugating/ligating activity is a nuclear binding partner to PCNA which is essential to numerous nuclear functions.

Goodman’s laboratory went on to demonstrate that membrane protein ubiquitination, including αSPI, is diminished in erythrocytes from Sickle Cell Disease patients. ^177,180 Furthermore, we demonstrated that this was due to decreased spectrin E2/E3 activity in SCD RBCs.¹⁷⁷ SCD RBCs are exposed to increased oxidative stress, with decreased protection by reduced glutathione, which results in cysteine oxidation and glutathiolation leading to blockage of αSpI C2071 (and other cysteines), and oxidative damage to other proteins.^{6–9,177,181–187} Goodman and colleagues have demonstrated that diminished mono-ubiquitination of αSpI has no impact upon spectrin dimer to tetramer interconversion¹⁸⁸ but results in the diminished ability of spectrin-4.1-actin¹⁸⁹ and spectrin-adducin-actin¹⁹⁰ complexes to dissociate at physiologic conditions. These effects, plus oxidation of actin leading to filaments which will not depolymerize^191–194, leads to the slow dissociation of the membrane skeleton^191,195 and is the molecular basis of the irreversibly sickle cell (ISC).¹⁸³ Caprio et al have found that diminished spectrin ubiquitination is also the basis for RBC rigidity in multiple organ dysfunction syndrome (MODS).¹⁹⁶

As explained in our previous reviews, and shown in Figure 7, there is every reason to believe that αSpII has the same chimeric E2/E3 activity as αSpI.^8,9 As this has been previously reviewed, we will focus on the reasons demonstrated by Figure 7. Human αSpII has a 16 amino acid segment in repeat 20 that contains a cysteine 2120 which is surrounded by the consensus E2 sequence found in all E2 enzymes. This stretch in αSpII has 63% identity to the same stretch in human αSpI (Figure 7A), and a 100% identity to the same stretch in αSpII from mouse, chicken and worm.⁹ There is a single conserved amino acid change in Drosophila that is distinct from the human version (Figure 7B). It will be a simple study to test the αSpII E2/E3 activity in vitro.

So why is the spectrin E2/E3 activity important for normal physiology and pathophysiology of all human cells? We already know that SPTA1 is present not only in RBCs, but also in the cytoplasm and nucleus of neurons and skeletal and cardiac muscle (see Spectrinome figures 4 and 6). While the human erythrocyte proteome contains approximately 2300 proteins,¹¹⁰ the human proteome will contain about ten times that number of proteins.⁸⁷ The number of Spectrinome proteins with 1st order interactions with SPTA1 are 137 (Supplementary Table 1), and these databases contain only about 75% of the human proteome. All of these proteins can potentially be ubiquitinated by αSpI. For SPTN1 the number of proteins in the 1st order Spectrinome is 183, again with a database which is about 75% complete. SPTAN2 is in all human cells except RBCs. We have demonstrated ubiquitination of αSpI and αSpII in rat hippocampal neurons in culture and in human brain slices from deceased Alzheimer’s, Parkinson’s, and Age matched control human brains. In Alzheimer’s and Parkinson’s disease both α-spectrins were major components of the ubiquitinated inclusions.^91,92

Homeostasis of every protein pathway discussed in this review can potentially be regulated by Spectrin’s chimeric E2/E3 activity. While we have demonstrated that RBC spectrin can be mono-ubiquitinated, and this regulates protein-protein interactions; ^6,189,190 examination of our earlier articles (ex, ref 6 Figure 1) shows a ladder of spectrin-ubiquitin adducts when RBC membranes are blotted with Ubiquitin antibodies. This suggests that while spectrin can mono-ubiquitinate itself, that this single ubiquitin can become a poly-ubiquitin chain. We would suggest that it is likely that spectrin’ s E2/E3 activity can lead to poly-ubiquitination, thereby involving proteasomes in the regulation of those pathways impacted by the various spectrin scaffolds. This is an exciting area for future investigation.

Sangerman et al studied the synthesis and turnover of spectrin isoform specific subunits in primary cultures of hippocampal neurons.⁹¹ What was found was quite interesting. The αSpIΣ1 and βSpIΣ2 erythroid subunits all turned over with a half-life of 16 to 24 minutes, independent of whether the spectrin subunits were in the soluble pool or the particulate pool. However, for the nonerythroid subunits αSpIIΣ1 and βSpIIΣ1 the turnover of the particulate (membrane or nucleo/cyto-membrane skeletal) forms was 30 to 34 minutes, but the turnover of the soluble forms turned over much slower: 80 (αSpII) and 53 minute (βSpII) half-life. Do these rates of turnover reflect the distribution of proteasomes in the cytoplasm versus nucleus, or membrane versus cyto- or nucleo-plasm? Spectrin could be keeping both the cytoplasmic and nuclear proteasomes very busy. This in uncharted territory for future investigation.

Calpain cleavage of αSpIIΣ1 between Tyr1176 and Gly1177 at the hypersensitive site, in response to Glutamate binding to the NMDR receptor and elevated Ca²⁺, is a normal part of regulating neuronal development and synaptic plasticity.^{80,81,83,197–199} But during brain injury caused by TBI, hypoxia-ischemia or neurodegeneration, Ca²⁺ increases to levels where in addition to the calpain cleavage of αSpII, we also see caspase 3 cleavage of both αSpII and βSpII leading to cell death.^83,198–200 How are the calpain spectrin signature breakdown products (SPDPs) replaced by new αSpII? Does this require ubiquitin directed proteasomal degradation of these membrane bound SBDPs? Is this also involved in control of synaptic plasticity? There are lots of studies to be done. Neurodegeneration and many other diseases discussed in this review, including the following section, are characterized by altered redox status. Does this cause altered spectrin E2/E3 activity in these non-erythroid cells and tissues, where the critical cysteines would again be oxidized or glutathiolated?

There is much to be done, but when you have a scaffold protein, representing 2-3% of all human cells, present in all cellular compartments, playing a myriad of functions, and this protein has the ability to ubiquitinate its partners, how could this not be central to normal and/or pathologic cell function?

Spectrin and Human Disease

In this section, we will focus on Human Disease caused by a spectrin specific genetic defect or diminished levels of the protein. We have given several examples in Table 5. Although a very interesting subject, we will not focus on genetic disorders related to spectrin binding partners. As an example, we refer the reader to several reviews that discuss the relationship of defects in ankyrin isoforms to human cardiomyopathies and neurologic disorders.^201–205

Table 5.

Spectrin Isoforms and Human Diseases

Gene Symbol	Disease	Comments
SPTA1	Hereditary Elliptocytosis (EL2)	Elliptical Osmotically Fragile RBCs
	Hereditary pyropoikilocytosis (HPP)	Spiculated Heat Sensitive Osmotically Fragile RBCs
	Hereditary Spherocytosis (HS3)	Spherical Osmotically Fragile RBCs
SPTNA1	Epileptic encephalopathy, early infantile, 5 (EIEE5)	Mental Retardation, Seizures, Developmental Delay, West Syndrome
	Fanconi Anemia (FA)	Bone marrow failure syndrome characterized by impaired DNA repair and predisposition to Cancer
	B-Cell Malignant Lymphoma (BCL)	85% of non-Hodgkin Lymphomas. Affects B Lymphocytes
SPTB1	Hereditary Elliptocytosis 3 (EL3)	Elliptical Osmotically Fragile RBCs
	Hereditary Spherocytosis (HS2)	Spherical Osmotically Fragile RBCs
SPTBN1	Beckwith-Wiedemann syndrome (BWS)	Macrosomia, Increased risk of Cancer
	Hepatocellular Carcinoma (HCC)	Liver Cancer
SPTBN2	Spinocerebellar ataxia 5 (SCA5)	Cerebellar Disorder with lack of Coordination of gait, hand, speech and eye movement
SPTBN4	Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND)	Congenital myopathy, central deafness, axonal & demyelinating neuropathy
SPTBN5	TBD	TBD

Open in a new tab

Defects in SPTA1 and SPTB1 lead to the well-known RBC disorders where red cells take on abnormal shapes, possess friable membrane skeletons and are osmotically fragile. Hereditary Elliptocytosis (HE) are a heterogeneous group of genetic disorders where the RBC takes on an extended oval or elliptical shape. The most common causative genetic defects are found near the n-terminus of αSpI (EL2) or the c-terminus of βSpI (EL3) and disrupt the head-to-head interaction of spectrin heterodimers leading to an inability to form tetramers.^206,207 In some cases, the genetic defect can be more distal from the n-terminus of αSpI, and be caused by stabilization of a closed dimer conformation leading to diminished spectrin tetramers.²⁰⁸ Most of HE patients are heterozygotes and have a mild form of the disease. Some patients are homozygous or compound heterozygotes and have a more severe form of this disorder that is referred to as Hereditary Pyropoikilocytosis (HPP) where the RBCs are oval and spiculated and heat sensitive.^206,207 HPP patients have a higher content of abnormal αSpI as compared to HE.

Hereditary Spherocytosis (HS) is also heterogeneous hemolytic anemia where the RBCs are round and osmotically fragile. Most cases demonstrate a partial deficiency in spectrin leading to blebbing off vesicles and loss of membrane surface area. The diminishment of spectrin can be due to direct genetic defects in α-spectrin (SPTA1), β-spectrin (SPTB1) or, alternatively in the proteins that are involved in linking spectrin to the bilayer (ankyrin (ANK1), band 3 (SLC4A1), and protein 4.2 (EPB42)).^206,207,209 There have also been cases of HS described that are caused by defects in the 4.1/actin binding domain of βSpI leading to diminished formation of the spectrin-4.1-actin ternary complex.^210,211

As discussed in the prior section dealing with the functions of spectrin in the nucleus, αSpII (SPTAN1) plays an essential scaffolding role in DNA interstrand crosslink repair and maintaining chromosomal stability. Diminished levels of αSpII (35-40% of normal) are found in cells from patients with the bone marrow failure disorder Fanconi’s Anemia.^124,133,136 The hallmarks of Fanconi’s anemia are bone marrow failure, inability to repair DNA damage and a higher likelihood of developing cancer.^{124,212–216} Given its role in DNA repair it is not surprising that diminished or mutationally altered αSpII will be found in various forms of human cancer. In fact, it has been suggested that αSpII plays a tumor suppressor role for a broad range of cancers.²¹⁷ One example is the observation of diminished αSpII in bone marrow samples from patients with acute myeloid leukemia.²¹⁸ Mutations in SPTAN1 have also been demonstrated to lead to early onset West syndrome, or Severe Early Infantile Epileptic Encephalopathy (EIEE5). EIEE5 is characterized by early onset seizures, brain atrophy, mental retardation, difficulties with walking, speech and vision.^219–221 The mutations in several cases were in the nucleation site that allows normal spectrin heterodimer formation.

SPTBN1, or βSpII, genetic defects lead to several human disorders including Hepatocellular Cancer.²²² As discussed earlier, βSpII serves an essential role in the TGF-β signaling pathway. Dysregulation of TGFβ signaling is thought to contribute to dysfunctional differentiation leading to the development of cancers. As mentioned above, βSpII associates with the Smad3/Smad4 complex and plays a role in its entry into the nucleus. This drives TGFβ-mediated tumor suppression. The defective or diminished βSPII leads to disruption of TGFβ signaling and has been demonstrated to play a key role in the development of gastrointestinal cancers. Zhi et al demonstrated that knockdown of βSpII expression led to stem cell-like features in hepatocellular carcinoma cells and to malignant tumor progression.²²³ Chen et al recently showed that βSPII expression correlates with the differentiation of hepatocytes in culture. They further demonstrated that hepatocyte differentiation induced by βSPII decreased the production of liver cancer stem cells.²²⁴. This suggests that enhancing the levels of βSpII in liver cancer stem cells could be an efficacious treatment strategy for treating hepatocellular carcinoma.

Ikeda et al have characterized the mutations in German, French and American families with spinocerebellar ataxia type 5 (SCA5).²²⁵ Interestingly, the American family was descended from the paternal grandfather of President Abraham Lincoln. What was found were mutations in the actin-binding domain of βSpIII in the German family and in repeat 3 in the American and French families. This group found a loss of the glutamate receptor (EAAT4) from the plasma membrane of Purkinje cells due to the defect in βSpIII.²²⁵ This would lead to altered glutamate signaling and may explain the characteristics of SCA5. These characteristics include: mildly progressive atrophy of the cerebellum, ataxia impacting gait, and slurred speech.

Several cases of mutations in βSpIV (SPTBN4 gene) result in a human neurodevelopmental disorder with hypotonia, neuropathy, and deafness (NEDHND).²²⁶ βIV-spectrin protein is known to be critical for securing Na+ channels to their position in the initial segment of an axon, as well as nodes of Ranvier.^227,228 In this regard, Kopp-Scheinpflug and Tempel have shown mutations in mice that affect the βIV-spectrin protein result in temporal alterations in central auditory neuronal signaling that could be a mechanism of auditory processing disorder.²²⁹ More recently, Liu et al.,²³⁰ have outlined the critical role of spectrin in hearing development and deafness. Not surprisingly, they found that specific spectrin subunits, namely, αII- and βII-spectrin, were critical for the structural organization of rodent hair cells. Further, βII-spectrin knockout mice demonstrated extreme deafness.

The observation that βIV-spectrin is important for the control of initial segment and nodal Na+ channel clustering provides insights into other sensory organ dysfunction that may result from key mutations. Although no specific forms of olfactory dysfunction have been associated with such mutations, the observations of Kosaka et al²³¹ suggest that such a relationship should exist. The main olfactory bulb is by-in-large anaxonic. Nonetheless, these investigators identified sodium channel clusters associated with βIV-spectrin ‘‘hot spots’’ on dendritic segments of external plexiform layer neurons in the rodent main olfactory bulb. Thus, it is intriguing to speculate that mutations that lead to channelopathies or altered cytoskeletal/scaffolding in this sensory organ would also lead to altered processing and dysfunction.

We have purposely focused these discussions on human diseases that have been linked to spectrin isoforms. Many of these assignments were based on prior work in animal models. Although we have not assigned a human disease to SPTBN5 in table 5, that could change soon. Usher Syndrome (USH) is the major cause of human deaf-blindness. One of the defective gene products causing a severe form of this disease (USH1B) is the actin-based motor protein: myosin VIIa. Mutant mice that are deficient in this motor protein provide a phenotype similar to the hearing defect observed in USH1 subjects. It has now been demonstrated that βSpV (SPTBN5) homodimers couple USH1 proteins to myosin VII actin-based motors; and could play a key role in USH1B.²³²

Postlude

Erythrocyte Spectrin was first described over 50 years ago by Marchesi and Steers,¹⁰ we are approaching 40 years since Goodman et al described “Spectrin-like molecules in non-erythroid cells”¹, and it has been over 30 years ago since Reiderer et al provided the first description of multiple spectrin isoforms.³⁷ The great abundance of publications in the field over the past 50 years made it challenging to describe the functions of spectrin isoforms in the cytoplasm and nucleus, and signaling between the two compartments, in a minireview. We found the spectrinome to be a useful tool for visualizing and considering the enormous number of roles played by these isoforms and hope that it is useful to workers in the field, as they chart their future studies. We have made enormous progress in understanding the role of these spectrin isoforms in cellular physiology and pathophysiology, and there is plenty that remains to be done by current and future spectrin researchers. With the enormity of five decades worth of information, portrayed by the spectrinome, we had to pick and choose examples to discuss. There are many elegant studies that we could not cover in this review, due to page limitations, and we hope you will understand that we have read and appreciate all of the outstanding work that has preceded this review.

Supplemental Material

Supplemental Table1 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(234.1KB, pdf)}

Supplemental material, Supplemental Table1 for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function by Steven R. Goodman, Daniel Johnson, Steven L. Youngentob and David Kakhniashvili in Experimental Biology and Medicine

Supplemental Material

Supplemental Table2 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(243.7KB, pdf)}

Supplemental material, Supplemental Table2 for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function by Steven R. Goodman, Daniel Johnson, Steven L. Youngentob and David Kakhniashvili in Experimental Biology and Medicine

Supplemental Material

Supplemental Table3 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(230.4KB, pdf)}

Supplemental material, Supplemental Table3 for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function by Steven R. Goodman, Daniel Johnson, Steven L. Youngentob and David Kakhniashvili in Experimental Biology and Medicine

Supplemental Material

Supplemental Table4 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(234.1KB, pdf)}

Supplemental material, Supplemental Table4 for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function by Steven R. Goodman, Daniel Johnson, Steven L. Youngentob and David Kakhniashvili in Experimental Biology and Medicine

Supplemental Material

Supplemental Table5 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(239KB, pdf)}

Supplemental material, Supplemental Table5 for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function by Steven R. Goodman, Daniel Johnson, Steven L. Youngentob and David Kakhniashvili in Experimental Biology and Medicine

Supplemental Material

Supplemental Table6 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(230.3KB, pdf)}

Supplemental material, Supplemental Table6 for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function by Steven R. Goodman, Daniel Johnson, Steven L. Youngentob and David Kakhniashvili in Experimental Biology and Medicine

Supplemental Material

Supplemental Table7 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(230.7KB, pdf)}

Supplemental material, Supplemental Table7 for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function by Steven R. Goodman, Daniel Johnson, Steven L. Youngentob and David Kakhniashvili in Experimental Biology and Medicine

Author Contributions

S.R. Goodman was responsible for the Spectrinome concept and contributed to the writing of all sections of this mini-review. D. Johnson did all of the bioinformatics work on the Spectrinome and wrote part of Constructing the Spectrinome section. S.L. Youngentob wrote part of the Spectrin and Human Disease section. D. Kakhniashvili did much of the RBC proteomic studies and spectrin E2/E3 studies that are described, and contributed to the construction and writing of the Why is Spectrin’s Chimeric E2/E3 Activity Important to Spectrin Isoforms Function? section.

DECLARATION OF CONFLICTING INTERESTS

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

National Institutes of Health (AA017823).

REFERENCES

1.Goodman SR, Zagon IS, Kulikowski RR. Identification of a spectrin-like protein in nonerythroid cells. Proc. Nat’l Acad. Sci. USA 1981; 78:7570–7574 [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Goodman SR, Shiffer KA. The spectrin membrane skeleton of normal and abnormal human erythrocytes: a review. Am. J. Physiol: Cell Physiol 1983; 244:C121–C141 [DOI] [PubMed] [Google Scholar]
3.Goodman SR, Zagon IS. Brain spectrin: A review. Brain Res. Bul. 1984; 13:813–832 [DOI] [PubMed] [Google Scholar]
4.Goodman SR, Krebs KE, Whitfield CF, Riederer BM, Zagon IS. Spectrin and related molecules. CRC. Critical Rev Biochem. 1988; 23:171–234 [DOI] [PubMed] [Google Scholar]
5.Zagon IS, Higbee R, Riederer BM, Goodman SR. Spectrin subtypes in mammalian brain: an immunoelectron microscopic study. J. Neurosci.1986; 6:2977–2986 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Kakhniashvili DG, Chaudhary T, Zimmer WE, Bencsath FA, Jardine I, Goodman SR. Spectrin is an E2 Ubiquitin Conjugating Enzyme. Biochemistry 2001; 40:11630–11642 [DOI] [PubMed] [Google Scholar]
7.Hsu J, Zimmer WE, Goodman Sr. Erythrocyte Spectrin’s Chimeric E2/E3 Ubiquitin Conjugating/Ligating Activity. Cell. and Molec. Biol. 2005; 51:187–193 [PubMed] [Google Scholar]
8.Hsu J, Goodman SR. Spectrin and Ubiquitination: A Review. Cell. and Molec. Biol. 2005; 51:OL801–OL807 [PubMed] [Google Scholar]
9.Goodman SR, Chapa RP, Zimmer WE. Spectrin’s Chimeric E2/E3 Enzymatic Activity. Exp. Biol. & Med. 2015; 240: 1039–1049 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Marchesi VT, Steers E. Selective solubilization of a protein component of the red cell membrane. Science 1968; 159(3811):203–204 [DOI] [PubMed] [Google Scholar]
11.Shotton DM, Burke BE, Branton D. The molecular structure of human erythrocyte spectrin. Biophysical and electron microscopic studies. J. Mol. Biol. 1979; 131(2):303–329 [DOI] [PubMed] [Google Scholar]
12.Goodman SR, Weidner SA. Binding of spectrin α2 – β2 tetramers to human erythrocyte membranes. J. Biol. Chem. 1980; 255:8082–8086 [PubMed] [Google Scholar]
13.Liu SC, Derick LH, Palek J. Visualization of the hexagonal lattice in the erythrocyte membrane skeleton. J Cell Biol. 1987; 104(3):527–536 [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Byers T.J., Branton D. Visualization of the protein associations in the erythrocyte membrane skeleton. Proc. Nat. Acad. Sci. USA, 1985; 82(18), pp. 6153–6157 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Shen B.W., Josephs R., Steck T.L. Ultrastructure of the intact skeleton of the human erythrocyte membrane. J. Cell Biol. 1986; 102(3), 997–1006 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Fowler V, Taylor DL. Spectrin plus band 4.1 cross-link actin. Regulation by micromolar calcium. J Cell Biol. 1980; 85(2):361–376 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Tyler JM, Hargreaves WR, Branton D. Purification of two spectrin-binding proteins: biochemical and electron microscopic evidence for site-specific reassociation between spectrin and bands 2.1 and 4.1. Proc. Nat’l. Acad. Sci. USA 1979; 76(10):5192–5196 [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Ungewickell E, Bennett PM, Calvert R, Ohanian V, Gratzer WB. In vitro formation of a complex between cytoskeletal proteins of the human erythrocyte. Nature 1979; 280(5725):811–814 [DOI] [PubMed] [Google Scholar]
19.Goodman SR, Yu J, Whitfield CF, Culp EN, Posnak EJ. Erythrocyte membrane skeletal protein bands 4.1 a and b are sequence-related phosphoproteins. J. Biol.Chem. 1982; 257(8):4564–4569 [PubMed] [Google Scholar]
20.Gardner K, Bennett V. Modulation of spectrin-actin assembly by erythrocyte adducin. Nature 1987; 328(6128):359–62 [DOI] [PubMed] [Google Scholar]
21.Mische SM, Mooseker MS, Morrow JS. Erythrocyte adducin: a calmodulin-regulated actin-bundling protein that stimulates spectrin-actin binding. J Cell Biol. 1987; 105: 2837–2845 [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Li X, Bennett V. Identification of the spectrin subunit and domains required for formation of spectrin/adducin/actin complexes. J. Biol. Chem.1996; 271(26):15695–702 [DOI] [PubMed] [Google Scholar]
23.Baines AJ. The spectrin-ankyrin-4.1-adducin membrane skeleton: adapting eukaryotic cells to the demands of animal life. Protoplasma 2010; 244(1-4):99–131 [DOI] [PubMed] [Google Scholar]
24.Bennett V, Stenbuck PJ, Identification and partial purification of ankyrin, the high affinity membrane attachment site for human erythrocyte spectrin. J. Biol. Chem. 1979; 254(7): 2533–41 [PubMed] [Google Scholar]
25.Yu J, Goodman SR. Syndeins: The spectrin-binding protein(s) of the human erythrocyte membrane. Proc. Nat’l. Acad. Sci. USA 1979; 76:2340–2344 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Bennett V, Stenbuck PJ. Association between ankyrin and the cytoplasmic domain of band 3 isolated from the human erythrocyte membrane. J. Biol.Chem.1980; 255(13):6424–6432 [PubMed] [Google Scholar]
27.Wallin R, Culp EN, Coleman DB, Goodman SR. A structural model of human erythrocyte band 2.1: alignment of chemical and functional Domains. Proc. Natl. Acad. Sci. USA 1984; 81:4095–4099 [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Bennett V, Baines AJ. Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. Physiol Rev 2001; 81:353–392 [DOI] [PubMed] [Google Scholar]
29.Mueller TJ, Morrison M. Glycoconnectin (PAS 2), a membrane attachment site for the human erythrocyte cytoskeleton. Prog Clin Biol Res. 1981; 56:95–9116 [PubMed] [Google Scholar]
30.Shiffer KA, Goodman SR. Protein 4.1: its association with the human erythrocyte membrane. Proc. Natl. Acad. Sci. USA. 1984; 81:4404–4408 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Glenney JR, Glenney P, Weber K. F-actin-binding and cross-linking properties of porcine brain fodrin, a spectrin-related molecule. J. Biol. Chem. 1982; 257(16):9781–9787 [PubMed] [Google Scholar]
32.Burridge K, Kelly T, Mangeat P. Nonerythrocyte spectrins: actin-membrane attachment proteins occurring in many cell types. J.Cell Biol. 1982; 95: 478–486 [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Bennett V, Davis J, Fowler WE. Brain spectrin, a membrane-associated protein related in structure and function to erythrocyte spectrin. Nature 1982; 299(5879):126–131 [DOI] [PubMed] [Google Scholar]
34.Repasky EA, Granger BL, Lazarides E. Widespread occurrence of avian spectrin in nonerythroid cells. Cell 1982; 29(3):821–833 [DOI] [PubMed] [Google Scholar]
35.Goodman SR, Zagon IS, Whitfield CF, Casoria LA, McLaughlin PJ, Laskiewicz T. A spectrin-like protein from mouse brain membranes: Immunological and structural correlations with erythrocyte spectrin. Cell Motility 1983; 3:635–647 [DOI] [PubMed] [Google Scholar]
36.Goodman SR, Zagon IS, Whitfield CF, Casoria LA, Shohet SB, Bernstein S, McLaughlin PJ, Laskiewicz TL. A spectrin-like protein from mouse brain membranes: phosphorylation of the 235,000 dalton subunit. Am. J. Physiol:Cell Physiol. 1984; 16:C61–C73 [DOI] [PubMed] [Google Scholar]
37.Riederer BM, Zagon IS, Goodman SR. Brain spectrin (240/235) and brain spectrin (240/235E): two distinct spectrin subtypes with different locations within mammalian neural cells. J. Cell Biol. 1986; 102:2088–2096 [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Goodman SR, Riederer BM, Zagon IS. Spectrin subtypes in mammalian brain. BioEssays 1986; 5:25–29 [DOI] [PubMed] [Google Scholar]
39.Goodman SR, Zagon IS, Riederer BM. Spectrin isoforms in mammalian brain. Brain Res. Bull. 1987; 18:787–792 [DOI] [PubMed] [Google Scholar]
40.Goodman SR, Zagon IS. The neural cell spectrin skeleton: A review. Am. J. Physiol: Cell Physiol 1986; 250:C347–C360 [DOI] [PubMed] [Google Scholar]
41.Goodman SR, Zagon IS. Brain spectrin: structure, location and function, a symposium overview. Brain Res. Bull. 1987; 18:773–776 [Google Scholar]
42.Riederer BM, Lopresti LL, Krebs KE, Zagon IS, Goodman SR. Brain spectrin (240/235) and brain spectrin (240/235E): Conservation of structure and location within mammalian neural tissue. Brain Res. Bull. 1988; 21:607–616 [DOI] [PubMed] [Google Scholar]
43.Zagon IS, Goodman SR. Absence of brain spectrin (240/235) in dendrites of mammalian brain. Brain Res. Bull. 1989; 23:19–24 [DOI] [PubMed] [Google Scholar]
44.Riederer BM, Zagon IS, Goodman SR. Brain spectrin (240/235) and brain spectrin (240/235E): differential expression during mouse brain development. J. Neurosci. 1987; 7:864–874 [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Zagon IS, Riederer BM, Goodman SR. Spectrin expression during mammalian brain ontogeny. Brain Res Bull 1987; 18:799–807 [DOI] [PubMed] [Google Scholar]
46.Zimmer WE, Ma Y, Zagon IS, Goodman SR. Developmental Expression of Brain β-Spectrin Isoform Messenger RNAs. Brain Res. Bull. 1992; 594:75–83 [DOI] [PubMed] [Google Scholar]
47.Levine J, Willard M. Fodrin: axonally transported polypeptides associated with the internal periphery of many cells. J. Cell Biol. 1981, 90(3) 631–642 [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Zimmer WE, Ma Y, Goodman SR. Tissue Distribution of Brain β-spectrin mRNAs. Brain Res. Bull. 1991; 27:187–193 [DOI] [PubMed] [Google Scholar]
49.Goodman SR, Zimmer WE, Clark MB, Zagon IS, Barker JE, Bloom ML. Brain spectrin: of mice and men. Brain Res. Bull. 1995; 36:593–606 [DOI] [PubMed] [Google Scholar]
50.Clark MB, Ma Y, Bloom M, Barker J, Zagon IS, Zimmer WE, Goodman SR. Brain α Erythroid Spectrin: Identification, compartmentalization, and β- Spectrin Associations. Brain Res. Bull. 1994; 663:223–226 [DOI] [PubMed] [Google Scholar]
51.Morrow JS, Marchesi VT. Self-assembly of spectrin oligomers in vitro: A basis for a dynamic cytoskeleton. J. Cell Biol. 1981; 88(2): 463–468 [DOI] [PMC free article] [PubMed] [Google Scholar]
52.Speicher DW, Davis G, Marchesi VT. Structure of Human Erythrocyte Spectrin, II. The Sequence of the a-I Domain. J. Biol. Chem. 1983; 258: 14938–14947 [PubMed] [Google Scholar]
53.Yan Y, Winograd E, Viel A, Cronin T, Harrison SC, Branton D. Crystal Structure of the repetitive segments of spectrin, Science 1993, 252: 2027–2030 [DOI] [PubMed] [Google Scholar]
54.Grum VL, Li D, MacDonald RI, Mondragon A, Structures of Two Repeats of Spectrin Suggest Models of Flexibility. Cell 1999, 98, 523–535 [DOI] [PubMed] [Google Scholar]
55.Ipsaro JJ, Harper SL, Messick TE, Marmorstein R, Mondragón A, Speicher DW. Crystal structure and functional interpretation of the erythrocyte spectrin tetramerization domain complex. Blood 2010, 115: 4843–4852 [DOI] [PMC free article] [PubMed] [Google Scholar]
56.Takeuchi M, Miyamoto H, Sako Y, Komizu H, Kusumi A. Structure of the erythrocyte membrane skeleton as observed by atomic force microscopy. Biophys. J. 1998; 74: 2171–2183 [DOI] [PMC free article] [PubMed] [Google Scholar]
57.Swihart AH, Mikrut JM, Ketterson JB, Macdonald RC. Atomic force microscopy of the erythrocyte membrane skeleton. J Microsc. 2001; 204(3):212–225 [DOI] [PubMed] [Google Scholar]
58.Brown JW, Bullitt E, Sriswasdi S, Harper S, Speicher DW, McKnight CJ. The physiological molecular shape of spectrin: a compact supercoil resembling a Chinese finger Trap. PLOS Comput Biol 2015; 11:e1004302. [DOI] [PMC free article] [PubMed] [Google Scholar]
59.Sahr KE, Laurila P, Kotula L, Scarpa AL, Coupal E, Leto TL, Linnenbach A.J., Winkelmann J.C., Speicher D.W., Marchesi V.T., Curtis P.J., Forget B.G. The complete cDNA and polypeptide sequences of human erythroid alpha-spectrin. J. Biol. Chem. 1990; 265(8):4434–4443 [PubMed] [Google Scholar]
60.Cioe L, Laurila P, Pacifico M, Krebs K, Goodman SR, Curtis PJ. Cloning and nucleotide sequence of a mouse erythrocyte-β spectrin cDNA. Blood 1987; 70(4):915–920 [PubMed] [Google Scholar]
61.Winkelmann JC, Chang JG, Tse WT, Scarpa AL, Marchesi VT, Forget BG. Full-length sequence of the cDNA for human erythroid beta-spectrin. J. Biol. Chem. 1990; 265(20):11827–32 [PubMed] [Google Scholar]
62.Moon RT., McMahon AP. Generation of diversity in nonerythroid spectrins. Multiple polypeptides are predicted by sequence analysis of cDNAs encompassing the coding region of human nonerythroid alpha-spectrin. J. Biol. Chem. 1990; J. Biol. Chem. 265:4427-4433:4427–4433 [PubMed] [Google Scholar]
63.Hu RJ., Watanabe M., Bennett V. Characterization of human brain cDNA encoding the general isoform of beta-spectrin. J. Biol. Chem. 1992; 267:18715–18722 [PubMed] [Google Scholar]
64.Ma Y, Zimmer WE, Riederer BM, Bloom ML, Barker JE, Goodman SR. The Complete Amino Acid Sequence for Brain β Spectrin (β fodrin): Relationship to Globin Sequences. Mol. Brain Res. 1993; 18:87–99 [DOI] [PubMed] [Google Scholar]
65.Winkelmann JC, Forget BG. Erythroid and nonerythroid spectrins. Blood 1993; 81:3173–3185 [PubMed] [Google Scholar]
66.Trave G, Lacombe P-J, Pfuhl M, Saraste M, Pastore A. Molecular mechanism of the calcium-induced conformational change in the spectrin EF-hands. EMBO Journal 1995; 14: 4922–4931 [DOI] [PMC free article] [PubMed] [Google Scholar]
67.Musacchio A, Noble M, Pauptit R, Wierenga R, Saraste M. Crystal structure of a Src-homology 3 (SH3) domain. Nature 1992; 359: 851–855 [DOI] [PubMed] [Google Scholar]
68.Fen S, Chen JK, Yu H, Simon JA, Schreiber SL. Two binding orientations for peptides to the Src SH3 domain: development of a general model for SH3-ligand interactions. Science 1994; 266:1241–1247 [DOI] [PubMed] [Google Scholar]
69.Mayer BJ. SH3 domains: complexity in moderation. J Cell Sci 2001; 114:1253–1263 [DOI] [PubMed] [Google Scholar]
70.Chang TC, Cubillos FF, Kakhniashvili DG, Goodman SR. Band 3 is a Target of Spectrin’s E2/E3 Activity: Implications for Sickle Cell Disease and Normal RBC Aging. Cell. and Molec. Biol. 2004; 50:171–177 [PubMed] [Google Scholar]
71.Chang TL, Cubillos FF, Kakhniashvili DG, Goodman SR. Ankyrin is a target of spectrin’s E2/E3 ubiquitin-conjugating/ligating activity. Cell. and Molec. Biol. 2004; 50:59–66 [PubMed] [Google Scholar]
72.Macias MJ, Musachhhio A, Ponstingl H, Nilges M, Saraste M, Oschkinat H. Structure of the pleckstrin homology domain from beta-spectrin. Nature 1994; 369: 675–677 [DOI] [PubMed] [Google Scholar]
73.Karinch AM, Zimmer WE, Goodman SR. The Identification and Sequence of the Actin-Binding Domain of Human Red Blood Cell β-Spectrin. J. Biol. Chem. 1990; 265:11833–11840 [PubMed] [Google Scholar]
74.Hartwig JH. Actin-binding proteins. 1. Spectrin super family, Protein Profile 1995; 2: 703–800 [PubMed] [Google Scholar]
75.Castresana J, Saraste M, Does Vav bind to F-actin through a CH domain? FEBS Lett. 1995; 374: 149–151 [DOI] [PubMed] [Google Scholar]
76.Djinovic Carugo K, Banuelos S, Saraste M, Crystal structure of a calponin homology domain, Nat. Struct. Biol. 1997; 4: 175–179 [DOI] [PubMed] [Google Scholar]
77.Banuelos S, Saraste M, Djinovic Carugo K, Structural comparisons of calponin homology domains: implications for actin binding. Structure 1998; 6: 1419–1431 [DOI] [PubMed] [Google Scholar]
78.Harris AS, Morrow JS, Proteolytic processing of human brain alpha spectrin (fodrin): identification of a hypersensitive site, J. Neurosci. 1988; 8: 2640–2651 [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Harris AS, Croall DE, Morrow JS. Calmodulin regulates fodrin susceptibility to cleavage by calcium-dependent protease I. J Biol Chem 1989; 264:17401–17408 [PubMed] [Google Scholar]
80.Nicolas G, Fournier CM, Galand C, Malbert-Colas L, Bournier O, Kroviarski Y, Bourgeois M, Camonis JH, Dhermy D, Grandchamp B, Lecomte MC. Tyrosine phosphorylation regulates alpha II spectrin cleavage by calpain. Mol Cell Biol 2002; 22:3527–3536 [DOI] [PMC free article] [PubMed] [Google Scholar]
81.Nedrelow JH, Cianci CD, Morrow JS, C-Src binds αII spectrin’s Src homology 3 (SH3) domain and blocks calpain susceptibility by phosphorylating Tyr1176. J Biol Chem 2003; 278:7725–7741 [DOI] [PubMed] [Google Scholar]
82.Rotter B, Kroviarski Y, Nicolas G, Dhermy D, Lecomte MC. AlphaII-spectrin is an in vitro target for caspase-2, and its cleavage is regulated by calmodulin binding, Biochem. J. 2004; 378: 161–168 [DOI] [PMC free article] [PubMed] [Google Scholar]
83.Glantz S.B., Cianci C.D., Iyer R., Pradhan D., Wang K.K., Morrow J.S., Sequential degradation of alphaII and betaII spectrin by calpain in glutamate or maitotoxin-stimulated cells, Biochemistry 2007; 46:502–513 [DOI] [PMC free article] [PubMed] [Google Scholar]
84.Fabregat A, Jupe S, Matthews L, Sidiroppoulos K, Gillespie M, Garapati P, Haw R, Jassal B, Korninger F, May B, Milacic M, Roca CD, Rothfels K, Sevilla C, Shamovsky V, Shorser S, Varusai T, Viteri G, Weiser J, Wu G, Stein L, Hermjakob H, D’Eustachio P. The Reactome Pathway Knowledgebase. Nucleic Acid Research 2019; 46(D1):D649–D655 [DOI] [PMC free article] [PubMed] [Google Scholar]
85.Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015; 1(6):417–425 [DOI] [PMC free article] [PubMed] [Google Scholar]
86.Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, von Mering C. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019; 47:D607–613. https://string-db.org/ [DOI] [PMC free article] [PubMed] [Google Scholar]
87.Thul PJ, et al. A subcellular map of the human proteome. Science 2017;356:820 [DOI] [PubMed]
88.Corsi D, Galluzzi L, Crinelli R, Magnani M. Ubiquitin is conjugated to the cytoskeletal protein alpha-spectrin in mature erythrocytes. J. Biol. Chem.1995; 270(15):8928–8935 [DOI] [PubMed] [Google Scholar]
89.Galluzi L, Nicholas G, Paiardini M, Magnani M, Lecomte MC. Identification of ubiquitinated repeats in human erythroid α-spectrin. Eur J Biochem 2000; 267:2812–2818 [DOI] [PubMed] [Google Scholar]
90.Galluzzi L, Paiardini M, Lecomte MC, Magnani M. Identification of the main ubiquitination site in human erythroid alpha-spectrin. FEBS Lett. 2001; 489(2-3):254–258 [DOI] [PubMed] [Google Scholar]
91.Sangerman J, Killilea AS, Chronister R, Pappolla MA, Goodman SR. α Spectrins are Major Ubiquitinated Proteins in Hippocampal Neurons and Components of Ubiquitinated Inclusions in Neurodegenerative Disorders. Brain Res. Bull. 2001; 54:405–511 [DOI] [PubMed] [Google Scholar]
92.Sangerman J, Kakhniashvili D, Brown A, Shartava A, Goodman SR. Spectrin Ubiquitination and Oxidative Stress: Potential Roles in Blood and Neurological Disorders. Cell Biol. Lett. 2001; 6:607–636 [PubMed] [Google Scholar]
93.Bennett V, Davis J. Erythrocyte ankyrin: Immunoreactive analogues are associated with mitotic structures in cultured cells and with microtubules in brain. Proc. Natl. Acad. Sci. USA. 1981; 78: 7550–7554 [DOI] [PMC free article] [PubMed] [Google Scholar]
94.Bennett V, Healy J. Membrane Domains Based on Ankyrin and Spectrin Associated with Cell–Cell Interactions. Cold Spring Harbor Persp. in Biol. 2009; 1: a003012. [DOI] [PMC free article] [PubMed] [Google Scholar]
95.Goodman SR, Casoria LA, Coleman DB, Zagon IS. Identification and location of Brain protein 4.1. Science 1984; 224:1433–1436 [DOI] [PubMed] [Google Scholar]
96.Krebs KE, Zagon IS, Goodman SR. Amelin: A 4.1-related spectrin binding protein found in neuronal cell bodies and dendrites. J. Neurosci. 1987; 7(12):3907–3914 [DOI] [PMC free article] [PubMed] [Google Scholar]
97.Zimmer WE, Zagon IS, Casoria LA, Goodman SR. Identification of an Amelin Isoform Located in Axons. Brain Res. Bull. 1992; 582:94–100 [DOI] [PubMed] [Google Scholar]
98.Krebs KE, Zagon IS, Sihag RK, Goodman SR. Brain protein 4.1 subtypes: A working hypothesis. BioEssays 1987; 6:274–279 [DOI] [PubMed] [Google Scholar]
99.Baines A J., Lu H -C, Bennett P M. The protein 4.1 family: Hub proteins in animals for organizing membrane proteins. Biochim. Biophys. Acta - Biomembranes, 2014; 1838, 605–619 [DOI] [PubMed] [Google Scholar]
100.Wu S, Sangerman J, Li M, Brough GH, Goodman SR, Stevens T. Essential Control of an endothelial cell Isoc by the spectrin membrane skeleton. J. Cell Biol. 2001; 154:1–1 [DOI] [PMC free article] [PubMed] [Google Scholar]
101.Wu S, Cioffi E, Alvarez D, Sayner S, Chen H, Cioffi D, King J, Creighton J, Townsley M, Goodman SR, Stevens T. Essential Role of a Ca²⁺ Selective, Store Operated Current (ISOC) in Endothelial Cell Permeability. Determination of the Vascular Leak Site. Circul. Res. 2005; 96:856–863 [DOI] [PubMed] [Google Scholar]
102.Cioffi DL, Wu S, Alexeyev M, Goodman SR, Zhu MX, Stevens T. Activation of the Endothelial Store-Operated/_socCa²⁺ Channel Requires Activation of Protein 4.1 with TRPC4. Circ. Res. 2005; 197:1164–1170 [DOI] [PubMed] [Google Scholar]
103.Davis L, Abdi K, Machius M, Brautigam C, Tomchick DR, Bennett V, Michaely P. Localization and structure of the ankyrin-binding site on β2-spectrin. J Biol Chem 2008; 284: 6982–6987 [DOI] [PMC free article] [PubMed] [Google Scholar]
104.Ipsaro JJ, Huang L, Mondragon A. Structures of the spectrin-ankyrin interaction binding domains. Blood 2009; Blood 113: 5385–5393 [DOI] [PMC free article] [PubMed] [Google Scholar]
105.Stabach PR, Simonović I, Ranieri MA, Aboodi MS, Steitz TA, Simonović M, Morrow JS. 2009. The structure of the ankyrin-binding site of β-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties. Blood 113: 5377–5384 [DOI] [PMC free article] [PubMed] [Google Scholar]
106.An X., Debnath G., Guo X., Liu S., Lux S.E., Baines A., Gratzer W., Mohandas N., Identification and functional characterization of protein 4.1R and actin-binding sites in erythrocyte beta spectrin: regulation of the interactions by phosphatidylinositol-4,5-bisphosphate, Biochemistry 2005; 44: 10681–10688 [DOI] [PubMed] [Google Scholar]
107.Zimmer WE, Zhao Y, Sikorski AF, Critz S, Sangerman J, Elferink L, Xu XS, Goodman SR. The Domain of β-Spectrin Responsible for Synaptic Vesicle Association is Essential for Synaptic Transmission. Brain Res. 2000; 881:18–27 [DOI] [PubMed] [Google Scholar]
108.Krebs KE, Prouty SM, Zagon IS, Goodman SR. The structural and functional relationship of RBC protein 4.1 to synapsin I. Am. J. Physiol. Cell Physiol. 1987; 22:C500–C505 [DOI] [PubMed] [Google Scholar]
109.Goodman SR, Kurdia A, Ammann L, Kakhniashvili D, Daescu O. The Human Red Blood Cell Proteome and Interactome. Exp. Biol. & Med. 2007; 232:1391–1408 [DOI] [PubMed] [Google Scholar]
110.Goodman SR, Daescu O, Kakhniashvili D, Zivanic M. The Proteomics and Interactomics of Human Erythrocytes. Exp. Biol. & Med. 2013; 238: 509–518 [DOI] [PubMed] [Google Scholar]
111.Machnicka B, Czogalla A, Hryniewicz-Jankowska A, Boguslawska DM, Grochowalska R, Heger E, Sikorski AF. Spectrins: A structural platform for stabilization and activation of membrane channels, receptors and transporters. Biochim. Biophys. Acta 2014; 1838: 620–634 [DOI] [PubMed] [Google Scholar]
112.Unsain N, Stefani FD, Cáceres A. The Actin/Spectrin Membrane-Associated Periodic Skeleton in Neurons. Front Synaptic Neurosci. 2018; 10:10. [DOI] [PMC free article] [PubMed] [Google Scholar]
113.Han B, Zhou R, Xia C, Zhuang X. Structural organization of the actin-spectrin-based membrane skeleton in dendrites and soma of neurons. Proc Natl Acad Sci U S A. 2017; 114(32):E6678–E6685 [DOI] [PMC free article] [PubMed] [Google Scholar]
114.Hirokawa N, Noda Y, Tanaka Y, Niwa S. Kinesin superfamily motor proteins and intracellular transport. Nature Reviews 2009; 10: 682–696 [DOI] [PubMed] [Google Scholar]
115.Takeda S, Yamazaki H, Seng D-H, Kanai Y, Terada S, Hirokawa N. Kinesin Superfamily Protein 3 (KIF3) Motor Transports Fodrin-associating Vesicles Important for Neurite Building. J. Cell Biol. 2000; 148: 1255–1265 [DOI] [PMC free article] [PubMed] [Google Scholar]
116.Beck KA, Buchanan JA, Malhotra V, Nelson WJ. Golgi spectrin: identification of an erythroid beta-spectrin homolog associated with the Golgi complex. J Cell Biol. 1994; 127(3):707–23 [DOI] [PMC free article] [PubMed] [Google Scholar]
117.Salcedo-Sicilia L, Granell S, Jovis M, Sicart A, Mato E, Johannes L, Balla T, Egea G. βIII Spectrin Regulates the Structural Integrity and the Secretory Protein Transport of the Golgi Complex. J. Biol. Chem. 2013; 228(4):2157–2166 [DOI] [PMC free article] [PubMed] [Google Scholar]
118.Olenick MA, Holzbaur ELF, Dynein activators and adaptors at a glance. J. Cell Sci. 2019; 132: jcs227132. [DOI] [PMC free article] [PubMed] [Google Scholar]
119.Holleran EA, Ligon LA, Tokito M, Stankewich MC, Morrow JS, Holzbaur ELF. βIII Spectrin Binds to the Arp1 Subunit of Dynactin. J. Biol. Chem. 2001; 276(39):36598–36605 [DOI] [PubMed] [Google Scholar]
120.Sikorski AF, Terlecki G, Zagon IS, Goodman SR. Synapsin I- mediated Interaction of Brain Spectrin with Small Synaptic Vesicles. J. Cell Bio. 1991; 114:313–318 [DOI] [PMC free article] [PubMed] [Google Scholar]
121.Sikorski AF, Goodman SR. The Effect of Synapsin I Phosphorylation Upon Binding of Synaptic Vesicles to Spectrin. Brain Res. Bull. 1991; 27:195–198 [DOI] [PubMed] [Google Scholar]
122.Sikorski A, Sangerman J, Goodman SR, Critz S. Spectrin (βSpllΣ1) is an essential component in synaptic transmission. Brain Res. 2000; 852:161–166 [DOI] [PubMed] [Google Scholar]
123.Goodman SR. Discovery of Nonerythroid Spectrin to the Demonstration of its Key Role in Synaptic Transmission. Brain Res. Bull; 1999; 50(5/6):345–346 [DOI] [PubMed] [Google Scholar]
124.Lambert MW. Spectrin and its interacting partners in nuclear structure and function. Exp. Biol. and Med. 2018; 243:507–524 [DOI] [PMC free article] [PubMed] [Google Scholar]
125.Zagon IS, McLaughlin PJ, Goodman SR. Localization of spectrin in mammalian brain. J. Neurosci. 1984; 4:3089–3100 [DOI] [PMC free article] [PubMed] [Google Scholar]
126.Borland K, Osawa S, Kew D, Coleman DB, Goodman SR, Hall PF. Identification of a spectrin-like protein in sertoli cells. Biol. Reprod. 1985; 32:1143–1156 [DOI] [PubMed] [Google Scholar]
127.Goodman SR, Zagon IS, Coleman DB, McLaughlin PJ. Spectrin expression in neuroblastoma cells. Brain Res. Bull. 1986; 16:597–602 [DOI] [PubMed] [Google Scholar]
128.Osawa S, Kew D, Borland K, Coleman DB, Goodman SR, Halls PF. Occurrence of spectrin-like protein in Y-1 adrenal tumor cells. Endocrinology 1986; 118:2458–2463 [DOI] [PubMed] [Google Scholar]
129.Isayama T, Goodman SR, Zagon IS. Spectrin Isoforms in the Mammalian Retina. J. Neurosci. 1991; 11:3531–3538 [DOI] [PMC free article] [PubMed] [Google Scholar]
130.Isayama T, Goodman SR, Zagon IS. Localization of Spectrin Isoforms in the Adult Heart. Cell & Tissue Research 1993; 274:127–133 [DOI] [PubMed] [Google Scholar]
131.Kumaresan KR, Hang B, Lambert MW. Human endonucleolytic incision of DNA 3’ and 5’ to a site-directed psoralen monoadduct and interstrand cross-link. J Biol Chem 1995; 270:30709–30716 [DOI] [PubMed] [Google Scholar]
132.McMahon LW, Walsh CE, Lambert MW. Human α spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex. J Biol Chem 1999; 274:32904–32908 [DOI] [PubMed] [Google Scholar]
133.Brois DW, McMahon LW, Ramos NL, Anglin LM, Walsh CE, Lambert MW. A deficiency in a 230 kDA DNA repair protein in Fanconi anemia complementation group A cells is corrected by the FANCA cDNA. Carcinogenesis 1999; 20:1845–1853 [DOI] [PubMed] [Google Scholar]
134.Kumaresan KR, Lambert MW. Fanconi anemia, complementation group A, cells are defective in ability to produce incisions at sites of psoralen interstrand cross-links. Carcinogenesis 2000; 21:741–751 [DOI] [PubMed] [Google Scholar]
135.McMahon LW, Sangerman J, Goodman SR, Lambert MW. Human Alpha Spectrin II, in Association with the FANCA, FANCC and FANCG Proteins, Binds to DNA Containing Psoralen Interstrand Cross-links. Biochemistry 2001; 40:7025–7034 [DOI] [PubMed] [Google Scholar]
136.Sridharan D, Brown M, Lambert WC, McMahon LW, Lambert MW. Nonerythroid alphaII spectrin is required for recruitment of FANCA and XPF to nuclear foci induced by DNA interstrand cross-links. Journal of Cell Science 2003; 116(Pt 5):823–835 [DOI] [PubMed] [Google Scholar]
137.Tripsianes K, Folkers GE, Ab E, Das D, Odijk H, Jaspers NGJ, Hoeijmakers JHJ, Kapten R, Boelens R. The structure of the human ERCC1/XPF interaction domains reveals a complementary role for the two proteins in nucleotide excision repair. Structure 2005; 13:1849–1858 [DOI] [PubMed] [Google Scholar]
138.Choi YJ, Ryu KS, Ko YM, Chae YK, Pleton JG, Wemmer DE, Choi BS. Biophysical characterization of the interaction domains and mapping of the contact residues in the XPF-ERCC1 complex. J Biol Chem 2005; 280:28644–28652 [DOI] [PubMed] [Google Scholar]
139.Kumaresan K, Sridharan D, McMahon L, Lambert MW. Deficiency in incisions produced by XPF at the site of a DNA interstrand cross-link in Fanconi anemia cells. Biochemistry 2007; 46:14359–14368 [DOI] [PubMed] [Google Scholar]
140.Lefferts JA, Wang C, Sridharan D, Baralt M, Lambert MW. The SH3 domain of alphaII spectrin is a target for the Fanconi anemia protein, FANCG. Biochemistry 2009; 48(2):254–263 [DOI] [PubMed] [Google Scholar]
141.McMahon LW, Zhang P, Sridharan DM, Lefferts JA, Lambert MW. Knockdown of αII spectrin in normal human cells by siRNA leads to chromosomal instability and decreased DNA interstrand cross-link repair. Biochem Biophys Res Commun 2009; 381:288–293 [DOI] [PMC free article] [PubMed] [Google Scholar]
142.Wang C, Lambert MW. The Fanconi anemia protein, FANCG, binds to the ERCC1-XPF endonuclease via its tetratricopeptide repeats and the central domain of ERCC1. Biochemistry 2010; 49:5560–5569 [DOI] [PMC free article] [PubMed] [Google Scholar]
143.de Winter JP, Joenje H. The genetic and molecular basis of Fanconi anemia. Mutat Res 2009; 668:11–19 [DOI] [PubMed] [Google Scholar]
144.Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet 2008; 42:301–334 [DOI] [PubMed] [Google Scholar]
145.de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 2005; 19:2100–2110 [DOI] [PubMed] [Google Scholar]
146.O’Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol 2010; 11:171–181 [DOI] [PMC free article] [PubMed] [Google Scholar]
147.Zhang P, Herbig U, Coffman F, Lambert MW. Non-erythroid alpha spectrin prevents telomere dysfunction after DNA interstrand cross-link damage. Nucleic Acids Res, 2013; 41:5321–5340. [DOI] [PMC free article] [PubMed] [Google Scholar]
148.Crisp M, Liu Q, Rous K, Rattner JB, Shanahan C, Burke B, Stahl PD, Hodzic D. Coupling of the nucleus and the cytoplasm: role of the LINC complex. J Cell Biol 2005; 172:41–53 [DOI] [PMC free article] [PubMed] [Google Scholar]
149.Lottersberger F, Karssemeijer N, Dimitrova N, de Lange T. 53BP1 and the LINC complex promote microtubule-dependent DSB mobility and DNA repair. Cell 2015; 163:880–893 [DOI] [PMC free article] [PubMed] [Google Scholar]
150.Lawrence KS, Tapley EC, Cruz VE, Li Q, Aung K, Hart KC, Schwartz TU, Starr DA, Engebrecht J. LINC Complexes promote homologous recombination in part through inhibition of nonhomologous end joining. J Cell Biol 2016; 215:801–821 [DOI] [PMC free article] [PubMed] [Google Scholar]
151.Stroud MJ. Linker of nucleoskeleton and cytoskeleton complex proteins in cardiomyopathy. Biophysical Reviews 2018; 10:1033–1051 [DOI] [PMC free article] [PubMed] [Google Scholar]
152.Haque F, Lloyd DJ, Smallwood DT, Dent CL, Shanahan CM, Fry CM, Trembath RC, Shackleton SUN1. Interacts with nuclear lamin A and cytoplasmic nesprins to provide a physical connection between the nuclear lamina and the cytoskeleton. Mol Cell Biol 2006; 26:3738–3751 [DOI] [PMC free article] [PubMed] [Google Scholar]
153.Lombardi ML, Jaalouk DE, Shanhan MC, Burke B, Roux KJ, Lammerding J. The interaction between nesprins and Sun proteins at the nuclear envelope is critical for force transmission between the nucleus and cytoskeleton. J Biol Chem 2011; 286:26743–26753 [DOI] [PMC free article] [PubMed] [Google Scholar]
154.Dechat T, Pfleghaar K, Sengupta K, Shimi T, Shumaker DK, Solimando L, Goldman RD. Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes Dev 2008; 22:832–853 [DOI] [PMC free article] [PubMed] [Google Scholar]
155.Goldman RD, Gruenbaum Y, Moir RD, Shumaker DK, Spann TP. Nuclear lamins: building blocks of nuclear architecture. Gene Dev 2002; 16:533–547 [DOI] [PubMed] [Google Scholar]
156.Gruenbaum Y., Medalia O. Lamins: the structure and protein complexes. Curr Opin Cell Biol 2015; 32:7–12 [DOI] [PubMed] [Google Scholar]
157.Bengtsson L, Wilson KL. Multiple and surprising new functions for emerin, a nuclear membrane protein. Curr Opin Cell Biol 2004; 16:73–79 [DOI] [PubMed] [Google Scholar]
158.Berk JM, Tifft KE, Wilson KL. The nuclear envelope LEM-domain protein emerin. Nucleus 2013; 4:1–17 [DOI] [PMC free article] [PubMed] [Google Scholar]
159.Holaska JM, Kowalski AM, Wilson SL. Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the inner nuclear membrane. PLoS Biol 2004; 2:1354–1362 [DOI] [PMC free article] [PubMed] [Google Scholar]
160.Sridharan DM, McMahon LW, Lambert MW. Alpha II-Spectrin interacts with five groups of functionally important proteins in the nucleus. Cell Biol. Internat. 2006; 30(11):866–878 [DOI] [PubMed] [Google Scholar]
161.Holaska JM, Wilson KL. An emerin ‘proteome’: purification of distinct emerin-containing complexes from HeLa cells suggests molecular basis for diverse roles including gene regulation, mRNA splicing, signalling, mechano-sensing and nuclear architecture. Biochemistry 2007; 46:8897–8908 [DOI] [PMC free article] [PubMed] [Google Scholar]
162.Gerace L, Huber MD. Nuclear lamina at the crossroads of the cytoplasm and nucleus. J Struct Biol 2012; 177:24–31 [DOI] [PMC free article] [PubMed] [Google Scholar]
163.Lammerding J, Schulze PC, Takahaski T, Kozlov S, Sullivan T, Kamm RD, Stewart CL, Lee RT. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Invest 2004; 113:370–378 [DOI] [PMC free article] [PubMed] [Google Scholar]
164.Lammerding J, Hsiao J, Schulze PC, Kazlov S, Stewart CL, Lee RT. Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells. J Cell Biol 2005; 170:781–791 [DOI] [PMC free article] [PubMed] [Google Scholar]
165.Dahl KN, Riberio AJS, Lammerding J. Nuclear shape, mechanics and mechanotransduction. Circ Res 2008; 102:1307–1318 [DOI] [PMC free article] [PubMed] [Google Scholar]
166.Dhal KN, Kalinowski A. Nucleoskeleton mechanics at a glance. J Cell Sci 2011; 124:675–678 [DOI] [PMC free article] [PubMed] [Google Scholar]
167.Martins RP, Finan JD, Guilak F, Lee DA. Mechanical regulation of nuclear structure and function. Annu Rev Biomed Eng 2012; 14:431–455 [DOI] [PMC free article] [PubMed] [Google Scholar]
168.Armiger TJ, Spagnol ST, Dahl KN. Nuclear mechanical resilience but not stiffness is modulated by αII-spectrin. J Biomech 2016; 49:3983–3989 [DOI] [PMC free article] [PubMed] [Google Scholar]
169.Zhang Y, Alexander PB, Wang XF. TGF-β Family Signaling in the Control of Cell Proliferation and Survival. Cold Spring Harb. Perspect. Biol. 2017;; 9(4): pii: a022145. [DOI] [PMC free article] [PubMed] [Google Scholar]
170.Machnicka B, Grochowalska R, Boguslawska DM, Sikorski AF, Lecomte MC. Spectrin-based skeleton as an actor in cell signaling. Cell Mol Life Sci 2012; 69:191–201 [DOI] [PMC free article] [PubMed] [Google Scholar]
171.Thenappan A, Shukkla V, Abdul Khalek FJ, Li Y, Shetty K, Liu P, Li L, Johnson RL, Johnson L, Mishra L. Loss of TGFβ adaptor protein β2SP leads to delayed liver regeneration in mice. Hepatology 2011; 53:1641–1650 [DOI] [PMC free article] [PubMed] [Google Scholar]
172.Metral S, Machnicka B, Bigot S, Colin Y, Dhermy D, Lecomte M-C. αII-Spectrin is critical for cell adhesion and cell cycle. J Biol Chem 2009; 284:2409–2418 [DOI] [PubMed] [Google Scholar]
173.Pollerberg GE, Schachner M, Davoust J. Differentiation state dependent surface mobilities of two forms of the neural cell adhesion molecule. Nature 1986; 324:462–465 [DOI] [PubMed] [Google Scholar]
174.Pollerberg GE, Burridge K, Krebs KE, Goodman SR, Schachner M. The 180 kD component of the neural cell adhesion molecule N-CAM is involved in cell-cell contacts and cytoskeleton-membrane interactions. Cell and Tissue Res. 1987; 250:227–236 [DOI] [PubMed] [Google Scholar]
175.Sytnyk V, Leshchyns’ka I, Schachner M. Neural Cell Adhesion Molecules of the Immunoglobulin Superfamily Regulate Synapse Formation, Maintenance, and Function. Trends in Neurosci. 2017; 40(5):295–308 [DOI] [PubMed] [Google Scholar]
176.Sytnyk V, Leshchyns’ka I, Nikonenko AG, Schachner M. NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex. J. Cell Biol. 2006; 174:1071–1085 [DOI] [PMC free article] [PubMed] [Google Scholar]
177.Chang TL, Kakhniashvili DG, Goodman SR. Spectrin’s E2/E3 Ubiquitin Conjugating/Ligating Activity is Diminished in Sickle Cells. Am. J. Hematol. 2005; 79:89–96 [DOI] [PubMed] [Google Scholar]
178.Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T. A Proteomics Approach to Identify Proliferating Cell Nuclear Antigen (PCNA)-binding Proteins in Human Cell Lysates. J. Biol. Chem. 2002; 277(43):40362–40368 [DOI] [PubMed] [Google Scholar]
179.Srivastava M, Chen Z, Zhang H, Tang M, Wang C, Jung SY, Chen J. Replisome Dynamics and Their Functional Relevance upon DNA Damage through the PCNA Interactome. Cell Reports 2018; 25:3869–3883 [DOI] [PMC free article] [PubMed] [Google Scholar]
180.Monteiro CA, Gibson XA, Shartava A, Goodman SR. Preliminary Characterization of a Structural Defect in Homozygous Sickled Cell Alpha Spectrin Demonstrated By A Rabbit Autoantibody. Am. J. Hematol. 1998; 58:200–205 [DOI] [PubMed] [Google Scholar]
181.Gibson XA, Shartava A, McIntyre J, Monteiro CA, Zhang Y, Shah A, Campbell N, Goodman SR. The Efficacy of Reducing Agents or Antioxidants in Blocking the Formation of Irreversibly Sickled Cells In Vitro. Blood 1998; 91(11):4373–4378 [PubMed] [Google Scholar]
182.Goodman SR, Pace BS, Shartava A. New Therapeutic Approaches to Sickle Cell Disease: Targeting RBC Membrane Oxidative Damage. Cell Mol. Biol. Lett. 1999; 3:403–411 [Google Scholar]
183.Goodman SR. The Role of the Membrane Skeleton in Formation of the Irreversibly Sickle Cell: A Review. Cell. & Mol. Biol. Lett. 1996; 1:105–112 [Google Scholar]
184.Shartava A, Shah AK, Goodman SR. N-acetylcysteine and Clotrimazole Inhibit Sickle Erythrocyte Dehydration Induced by 1-Chloro – 2,4-Dinitrobenzene. Am. J. Hemat. 1999; 62:19–24 [DOI] [PubMed] [Google Scholar]
185.Shartava A, McIntyre J, Shah AK, Goodman SR. The Gardos Channel is Responsible for CDNB Induced Dense Sickle Cell Formation. Amer. J. Hematol. 2000; 64(3):184–189 [DOI] [PubMed] [Google Scholar]
186.Pace BS, Shartava A, Pack-Mabien A, Mulekar M, Ardia A, Goodman SR. Effects of N-Acetylcysteine on Vaso-occlusive Episodes in Sickle Cell Disease. Am. J. Hematol. 2003; 73:26–32 [DOI] [PubMed] [Google Scholar]
187.Goodman SR, Pace BS, Daescu O, Hansen KC, D’Alessandro A, Yang X, Glatt SJ. Multiomic Candidate Biomarkers For Clinical Manifestations Of Sickle Cell Severity: Acquiring Validated Biomarkers For Precision Medicine. Exp. Biol. & Med. 2016; 241:772–781 [DOI] [PMC free article] [PubMed] [Google Scholar]
188.Riahi MH, Kakhniashvili DG, Goodman SR. Ubiquitination of Red Blood Cell α-Spectrin Does Not Effect Heterodimer Formation. Am. J. Hematol. 2005; 78:281–287 [DOI] [PubMed] [Google Scholar]
189.Ghatpande SG, Goodman SR. Ubiquitination of spectrin regulates the erythrocyte spectrin-protein 4.1-actin ternary complex dissociation: implications for sickle cell membrane skeleton. Cell Mol Biol 2004; 50:67–74 [PubMed] [Google Scholar]
190.Mishra R, Goodman SR. Ubiquitination of Spectrin Regulates the Dissociation of the Spectrin-Adducin-F-Actin Ternary Complex In Vitro. Cell Mol. Biol. 2004; 50:75–80 [PubMed] [Google Scholar]
191.Shartava A, Monteiro CA, Bencsath FA, Schneider K, Chait BT, Gussio R, Casoria- Scott LA, Shah AK, Heuerman CA, Goodman SR. A Posttranslational Modification of β-Actin Contributes to the Slow Dissociation of the Spectrin-Protein 4.1-Actin Complex of Irreversibly Sickled Cells. J. Cell Biol. 1995; 128:805–815 [DOI] [PMC free article] [PubMed] [Google Scholar]
192.Bencsath FA, Shartava A, Monteiro CA, Goodman SR. Identification of the β-Actin Disulfide-Linked Peptide Which Leads to the Slow Dissociation of the Irreversibly Sickled Membrane Skeleton. Biochemistry 1996; 35:4403–4408 [DOI] [PubMed] [Google Scholar]
193.Shartava A, Korn W, Shah AK, Goodman SR. Irreversibly Sickled Cell β-Actin: Defective Filament Formation. Am. J. Hematol.1997; 55:97–103 [DOI] [PubMed] [Google Scholar]
194.Abraham A, Bencsath FA, Shartava A, Kakhniashvili DG, Goodman SR. Preparation of irreversibly sickled cell β-actin from normal red blood cell β-actin. Biochemistry 2002; 41:292–296 [DOI] [PubMed] [Google Scholar]
195.Shartava A, Miranda P, Shah A, Montiero CA, Goodman SR. High Density Sickle Cell Erythrocyte Core Membrane Skeletons Demonstrate Slow Temperature Dependent Dissociation. Am. J. Hematol. 1996; 51:215–220 [DOI] [PubMed] [Google Scholar]
196.Caprio K, Condon MR, Deitch EA, Xu DZ, Feketova E, Machiedo GW. Alteration of alpha-spectrin ubiquitination after hemorrhagic shock. Amer. J. of Surgery 2008; 196(5):663–669 [DOI] [PMC free article] [PubMed] [Google Scholar]
197.Huh GY, Glant SB, Je S, Morrow JS, Kim JH. Calpain proteolysis of αII-spectrin in the normal adult human brain. Neurosci Lett 2001; 316:41–44 [DOI] [PubMed] [Google Scholar]
198.Pike BR, Flint J, Dutta S, Johnson E, Wang KKW, Hayes RL. Accumulation of non-erythroid αII-spectrin and calpain-cleaved αII-spectrin breakdown products in cerebrospinal fluid after traumatic brain injury in rats. J Neurochem. 1997; 78:1297–1306 [DOI] [PubMed] [Google Scholar]
199.Czogalla A, Sikorski AF. Spectrin and calpain: a ‘target’ and ‘sniper’ in the pathology of neuronal cells. Cell Mol. Life Sci. 2001; 62:1913–1924 [DOI] [PMC free article] [PubMed] [Google Scholar]
200.Rotter B, Kroviarski Y, Nicholas G, Dhermy D, Lecomte MC. AlphaII-spectrin is an in vitro target for caspase-2, and its cleavage is regulated by calmodulin binding. Biochem J 2004; 378:161–168 [DOI] [PMC free article] [PubMed] [Google Scholar]
201.Baines AJ, Pinder JC. The spectrin-associated cytoskeleton in mammalian heart. Frontiers in Bioscience: a Journal and Virtual Library 2005; 10:3020–3033 [DOI] [PubMed] [Google Scholar]
202.Bennett V, Healy J. Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin. Trends Mol. Med. 2007; 14: 28–36 [DOI] [PubMed] [Google Scholar]
203.Cunha SR, Mohler PJ. Ankyrin protein networks in membrane formation and stabilization. J Cell Mol Med. 2009; 13:4364–76 [DOI] [PMC free article] [PubMed] [Google Scholar]
204.Zhang R, Zhang CY, Zhao Q, Li DH. Spectrin: Structure, function and disease. Science China: Life Sciences 2013; 56(12):1076–1085 [DOI] [PubMed] [Google Scholar]
205.Derbala M, Guo AS, Mohler PJ, Smith SA. The role of βII spectrin in cardiac health and disease. Life Sci 2018; 192:278–285 [DOI] [PMC free article] [PubMed] [Google Scholar]
206.Delaunay J, Dhermy D. Mutations involving the spectrin heterodimer contact site: Clinical expression and alterations in specific function. 1993; Semin. Hematol. 30(1):21–33 [PubMed] [Google Scholar]
207.Gallagher PG. Abnormalities of the erythrocyte membrane. Pediatr Clin North Am. 2013. Dec; 60(6):1349–1362 [DOI] [PMC free article] [PubMed] [Google Scholar]
208.Sriswasdi S, Harper SL, Tang H.-, Gallagher PG, Speicher DW. Probing large conformational rearrangements in wild-type and mutant spectrin using structural mass spectrometry. Proc. Natl. Acad. Sci. U S A. 2014; 111(5):1801–1806 [DOI] [PMC free article] [PubMed] [Google Scholar]
209.He B, -J, Liao L, Deng Z, -F, Tao Y, -F, Xu Y, -C, Lin F, -Q. Molecular Genetic Mechanisms of Hereditary Spherocytosis: Current Perspectives. Acta Haematol. 2018; 139:60–66 [DOI] [PubMed] [Google Scholar]
210.Goodman SR, Shiffer KA, Casoria LA, Eyster ME. Identification of the molecular defect in the erythrocyte membrane skeleton of some kindreds with hereditary spherocytosis. Blood 1982; 60:772–784 [PubMed] [Google Scholar]
211.Becker PS, Morrow JS, Lux SE. Abnormal oxidant sensitivity and beta-chain structure of spectrin in hereditary spherocytosis associated with defective spectrin-protein 4.1 binding. J Clin. Invest. 1987; 80:557–565 [DOI] [PMC free article] [PubMed] [Google Scholar]
212.Alter BP. Cancer in Fanconi anemia, 1927-2001. Cancer 2003; 97:425–440 [DOI] [PubMed] [Google Scholar]
213.Mathew CG. Fanconi anaemia genes and susceptibility to cancer. Oncogene 2006; 25:5875–5884 [DOI] [PubMed] [Google Scholar]
214.Kim H, D’andrea AD. Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev 2012; 26:1393–1408 [DOI] [PMC free article] [PubMed] [Google Scholar]
215.Brosh RM, Jr, Bellani M, Liu Y, Seidman MN. Fanconi anemia: a DNA repair disorder characterized by accelerated decline of the hematopoietic system cell compartment and other features of aging. Ageing Res Rev 2017; 33:67–75 [DOI] [PMC free article] [PubMed] [Google Scholar]
216.Mamrak NE, Shimamura A, Howlell NG. Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia. Blood Rev 2017; 31:93–99 [DOI] [PMC free article] [PubMed] [Google Scholar]
217.Ackermann A, Brieger A. The role of Nonerythroid Spectrin αII in Cancer. Journal of Oncology 2019; Article ID 7079604, 14 pages [DOI] [PMC free article] [PubMed]
218.Gorman EB, Chen L, Albanese J, Ratech H. Pattern of spectrin expression in B-cell lymphomas: loss of spectrin isoforms is associated with nodule-forming and germinal center-related lymphomas. Mod Pathol 2007; 20:1245–1252 [DOI] [PubMed] [Google Scholar]
219.Wang Y, TJ, Nelson AD, Glanowska K, Murphy GC, Jenkins PM, Parent JM. Critical roles of αII spectrin in brain development and epileptic encephalopathy. J Clin. Invest. 2018; 128:760–773 [DOI] [PMC free article] [PubMed] [Google Scholar]
220.Syrbe S, Harms FL, Parrini E, Montomoli M, Mutze U, Helbig KL, Polster T, Albrecht B, Bernbeck U, van Binsbergen E, Biskup S, Burglen L, Denecke J, Heron B, Heyne HO, Hoffmann GF, Hornemann F, Matsushige T, Matsuura R, Kato M, Korenke GC, Kuechler A, Lammer C, Merkenschlager A, Mignot C, Ruf S, Nakashima M, Saitsu H, Stamberger H, Pisano T, Tohyama J, Weckhuysen S, Werckx W, Wickeart J, Mari F, Verbeek NE, Moller RS, Koeleman B, Matsumoto N, Dobyns WB, Battaglia D, Lemke JR, Kutsche K, Guerrini R. Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy. Brain 2017; 140:2322–2336 [DOI] [PMC free article] [PubMed] [Google Scholar]
221.Tohyama J, Nakashima M, Nabatame S, Gaik-Siew C, Miyata R, Rener-Primec Z, Kato M, Matsumoto N, Saitsu H. SPTAN1: encephalopathy: distinct phenotypes and genotypes. J Hum.Genet. 2015; 60:167–173 [DOI] [PubMed] [Google Scholar]
222.Chen J, Shukla V, Farci P, Andricovich J, Jogunoori W, Kwong LN, Katz LH, Sheety K, Rashid A, Su X, White J, Li L, Wang AY, Blechacz B, Raju GS, Davila M, Nguyen B-N, Stroehlein JR, Chen J, Kim SS, Levin H, Machida K, Tsukamoto H, Michaely P, Tzatsos A, Mishra B, Amber R, Mishra L. Loss of the transforming growth factor-β effector β2-spectrin promotes genomic instability. Hepatology 2017; 65:678–693 [DOI] [PMC free article] [PubMed] [Google Scholar]
223.Zhi X, Lin L, Yang S, Bhuvaneshwar K, Wang H, Gusev Y, Lee MH, Kallakury B, Shivapurkar N, Cahn K, Tian X, Marshall JL, Byers SW, He AR. βII-Spectrin (SPTBN1) suppresses progression of hepatocellular carcinoma and Wnt signaling by regulation of Wnt inhibitor kallistatin. Hepatology. 2015. Feb; 61:598–612 [DOI] [PMC free article] [PubMed] [Google Scholar]
224.Chen Y, Meng L, Shang H, Dou Q, Lu Z, Liu L, Wang Z, He X, Song Y. β2 spectrin-mediated differentiation repressed the properties of liver cancer stem cells through β-catenin. Cell Death and Disease 2018; 9:424. [DOI] [PMC free article] [PubMed] [Google Scholar]
225.Ikeda Y, Dick KA, Weatherspoon MR, Gincel D, Armbrust KR, Dalton JC, Stevanin G, Dürr A, Zühlke C, Bürk K, Clark B, Brice A, Rothstein JD, Schut LJ, Day JW, Ranum LPW. Spectrin mutations cause spinocerebellar ataxia type 5. Nature Genetics 2006; 38(2):184–190 [DOI] [PubMed] [Google Scholar]
226.Wang CC, Ortiz-González XR, Yum SW, Gill SM, White A, Kelter E, Seaver LH, Lee S, Wiley G, Gaffney PM, Wierenga KJ, Rasband MN. βIV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hyptonia, and Motor Axonal Neuropathy. Am. J. Human Genet. 2018; 102:1158–1168 [DOI] [PMC free article] [PubMed] [Google Scholar]
227.Komada M, Soriano P. [Beta]IV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier. J Cell Biol. 2002; 156:337–348 [DOI] [PMC free article] [PubMed] [Google Scholar]
228.Uemoto Y, Suzuki S, Terada N, Ohno N, Ohno S, Yamanaka S, Komada M, Specific role of the truncated bIV-spectrin S6 in sodium channel clustering at axon initial segments and nodes of Ranvier. 2007; J. Biol. Chem. 282: 6548–6555 [DOI] [PubMed] [Google Scholar]
229.Kopp-Scheinpflug C, Tempel BL. Decreased temporal precision of neuronal signaling as a candidate mechanism of auditory processing disorder. Hear Res. 2015; 330(Pt B):213–220 [DOI] [PMC free article] [PubMed] [Google Scholar]
230.Liu Y, Qi J, Chen X, Tang M, Chu C, Zhu W, Li H, Tian C, Yang G, Zhong C, Zhang Y, Ni G, He S, Chai R, Zhong G. Critical role of spectrin in hearing development and deafness. Science Advances 2019; 5(4):1–9 [DOI] [PMC free article] [PubMed] [Google Scholar]
231.Kosaka T, Komada M, Kosaka K. Sodium channel cluster, bIV-spectrin and ankyrinG positive ‘‘hot spots’’ on dendritic segments of parvalbumin-containing neurons and some other neurons in the mouse and rat main olfactory bulbs. Neurosci. Res. 2008; 62: 176–186 [DOI] [PubMed] [Google Scholar]
232.Papal S, Cortese M, Legendre K, Sorusch N, Dragavon J, Sahly I, Shorte S, Wolfrum U, Petit C, El-Amraoui A, The giant spectrin βV couples the molecular motors to phototransduction and Usher syndrome type I proteins along their trafficking route, Human Mol. Gen. 2013; 22: 3773–3788 [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Table1 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(234.1KB, pdf)}

Supplemental Table2 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(243.7KB, pdf)}

Supplemental Table3 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(230.4KB, pdf)}

Supplemental Table4 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(234.1KB, pdf)}

Supplemental Table5 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(239KB, pdf)}

Supplemental Table6 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(230.3KB, pdf)}

Supplemental Table7 - Supplemental material for The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Click here for additional data file.^{(230.7KB, pdf)}

[bibr1-1535370219867269] 1.Goodman SR, Zagon IS, Kulikowski RR. Identification of a spectrin-like protein in nonerythroid cells. Proc. Nat’l Acad. Sci. USA 1981; 78:7570–7574 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr2-1535370219867269] 2.Goodman SR, Shiffer KA. The spectrin membrane skeleton of normal and abnormal human erythrocytes: a review. Am. J. Physiol: Cell Physiol 1983; 244:C121–C141 [DOI] [PubMed] [Google Scholar]

[bibr3-1535370219867269] 3.Goodman SR, Zagon IS. Brain spectrin: A review. Brain Res. Bul. 1984; 13:813–832 [DOI] [PubMed] [Google Scholar]

[bibr4-1535370219867269] 4.Goodman SR, Krebs KE, Whitfield CF, Riederer BM, Zagon IS. Spectrin and related molecules. CRC. Critical Rev Biochem. 1988; 23:171–234 [DOI] [PubMed] [Google Scholar]

[bibr5-1535370219867269] 5.Zagon IS, Higbee R, Riederer BM, Goodman SR. Spectrin subtypes in mammalian brain: an immunoelectron microscopic study. J. Neurosci.1986; 6:2977–2986 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr6-1535370219867269] 6.Kakhniashvili DG, Chaudhary T, Zimmer WE, Bencsath FA, Jardine I, Goodman SR. Spectrin is an E2 Ubiquitin Conjugating Enzyme. Biochemistry 2001; 40:11630–11642 [DOI] [PubMed] [Google Scholar]

[bibr7-1535370219867269] 7.Hsu J, Zimmer WE, Goodman Sr. Erythrocyte Spectrin’s Chimeric E2/E3 Ubiquitin Conjugating/Ligating Activity. Cell. and Molec. Biol. 2005; 51:187–193 [PubMed] [Google Scholar]

[bibr8-1535370219867269] 8.Hsu J, Goodman SR. Spectrin and Ubiquitination: A Review. Cell. and Molec. Biol. 2005; 51:OL801–OL807 [PubMed] [Google Scholar]

[bibr9-1535370219867269] 9.Goodman SR, Chapa RP, Zimmer WE. Spectrin’s Chimeric E2/E3 Enzymatic Activity. Exp. Biol. & Med. 2015; 240: 1039–1049 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr10-1535370219867269] 10.Marchesi VT, Steers E. Selective solubilization of a protein component of the red cell membrane. Science 1968; 159(3811):203–204 [DOI] [PubMed] [Google Scholar]

[bibr11-1535370219867269] 11.Shotton DM, Burke BE, Branton D. The molecular structure of human erythrocyte spectrin. Biophysical and electron microscopic studies. J. Mol. Biol. 1979; 131(2):303–329 [DOI] [PubMed] [Google Scholar]

[bibr12-1535370219867269] 12.Goodman SR, Weidner SA. Binding of spectrin α2 – β2 tetramers to human erythrocyte membranes. J. Biol. Chem. 1980; 255:8082–8086 [PubMed] [Google Scholar]

[bibr13-1535370219867269] 13.Liu SC, Derick LH, Palek J. Visualization of the hexagonal lattice in the erythrocyte membrane skeleton. J Cell Biol. 1987; 104(3):527–536 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr14-1535370219867269] 14.Byers T.J., Branton D. Visualization of the protein associations in the erythrocyte membrane skeleton. Proc. Nat. Acad. Sci. USA, 1985; 82(18), pp. 6153–6157 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr15-1535370219867269] 15.Shen B.W., Josephs R., Steck T.L. Ultrastructure of the intact skeleton of the human erythrocyte membrane. J. Cell Biol. 1986; 102(3), 997–1006 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr16-1535370219867269] 16.Fowler V, Taylor DL. Spectrin plus band 4.1 cross-link actin. Regulation by micromolar calcium. J Cell Biol. 1980; 85(2):361–376 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr17-1535370219867269] 17.Tyler JM, Hargreaves WR, Branton D. Purification of two spectrin-binding proteins: biochemical and electron microscopic evidence for site-specific reassociation between spectrin and bands 2.1 and 4.1. Proc. Nat’l. Acad. Sci. USA 1979; 76(10):5192–5196 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr18-1535370219867269] 18.Ungewickell E, Bennett PM, Calvert R, Ohanian V, Gratzer WB. In vitro formation of a complex between cytoskeletal proteins of the human erythrocyte. Nature 1979; 280(5725):811–814 [DOI] [PubMed] [Google Scholar]

[bibr19-1535370219867269] 19.Goodman SR, Yu J, Whitfield CF, Culp EN, Posnak EJ. Erythrocyte membrane skeletal protein bands 4.1 a and b are sequence-related phosphoproteins. J. Biol.Chem. 1982; 257(8):4564–4569 [PubMed] [Google Scholar]

[bibr20-1535370219867269] 20.Gardner K, Bennett V. Modulation of spectrin-actin assembly by erythrocyte adducin. Nature 1987; 328(6128):359–62 [DOI] [PubMed] [Google Scholar]

[bibr21-1535370219867269] 21.Mische SM, Mooseker MS, Morrow JS. Erythrocyte adducin: a calmodulin-regulated actin-bundling protein that stimulates spectrin-actin binding. J Cell Biol. 1987; 105: 2837–2845 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr22-1535370219867269] 22.Li X, Bennett V. Identification of the spectrin subunit and domains required for formation of spectrin/adducin/actin complexes. J. Biol. Chem.1996; 271(26):15695–702 [DOI] [PubMed] [Google Scholar]

[bibr23-1535370219867269] 23.Baines AJ. The spectrin-ankyrin-4.1-adducin membrane skeleton: adapting eukaryotic cells to the demands of animal life. Protoplasma 2010; 244(1-4):99–131 [DOI] [PubMed] [Google Scholar]

[bibr24-1535370219867269] 24.Bennett V, Stenbuck PJ, Identification and partial purification of ankyrin, the high affinity membrane attachment site for human erythrocyte spectrin. J. Biol. Chem. 1979; 254(7): 2533–41 [PubMed] [Google Scholar]

[bibr25-1535370219867269] 25.Yu J, Goodman SR. Syndeins: The spectrin-binding protein(s) of the human erythrocyte membrane. Proc. Nat’l. Acad. Sci. USA 1979; 76:2340–2344 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr26-1535370219867269] 26.Bennett V, Stenbuck PJ. Association between ankyrin and the cytoplasmic domain of band 3 isolated from the human erythrocyte membrane. J. Biol.Chem.1980; 255(13):6424–6432 [PubMed] [Google Scholar]

[bibr27-1535370219867269] 27.Wallin R, Culp EN, Coleman DB, Goodman SR. A structural model of human erythrocyte band 2.1: alignment of chemical and functional Domains. Proc. Natl. Acad. Sci. USA 1984; 81:4095–4099 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr28-1535370219867269] 28.Bennett V, Baines AJ. Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. Physiol Rev 2001; 81:353–392 [DOI] [PubMed] [Google Scholar]

[bibr29-1535370219867269] 29.Mueller TJ, Morrison M. Glycoconnectin (PAS 2), a membrane attachment site for the human erythrocyte cytoskeleton. Prog Clin Biol Res. 1981; 56:95–9116 [PubMed] [Google Scholar]

[bibr30-1535370219867269] 30.Shiffer KA, Goodman SR. Protein 4.1: its association with the human erythrocyte membrane. Proc. Natl. Acad. Sci. USA. 1984; 81:4404–4408 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr31-1535370219867269] 31.Glenney JR, Glenney P, Weber K. F-actin-binding and cross-linking properties of porcine brain fodrin, a spectrin-related molecule. J. Biol. Chem. 1982; 257(16):9781–9787 [PubMed] [Google Scholar]

[bibr32-1535370219867269] 32.Burridge K, Kelly T, Mangeat P. Nonerythrocyte spectrins: actin-membrane attachment proteins occurring in many cell types. J.Cell Biol. 1982; 95: 478–486 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr33-1535370219867269] 33.Bennett V, Davis J, Fowler WE. Brain spectrin, a membrane-associated protein related in structure and function to erythrocyte spectrin. Nature 1982; 299(5879):126–131 [DOI] [PubMed] [Google Scholar]

[bibr34-1535370219867269] 34.Repasky EA, Granger BL, Lazarides E. Widespread occurrence of avian spectrin in nonerythroid cells. Cell 1982; 29(3):821–833 [DOI] [PubMed] [Google Scholar]

[bibr35-1535370219867269] 35.Goodman SR, Zagon IS, Whitfield CF, Casoria LA, McLaughlin PJ, Laskiewicz T. A spectrin-like protein from mouse brain membranes: Immunological and structural correlations with erythrocyte spectrin. Cell Motility 1983; 3:635–647 [DOI] [PubMed] [Google Scholar]

[bibr36-1535370219867269] 36.Goodman SR, Zagon IS, Whitfield CF, Casoria LA, Shohet SB, Bernstein S, McLaughlin PJ, Laskiewicz TL. A spectrin-like protein from mouse brain membranes: phosphorylation of the 235,000 dalton subunit. Am. J. Physiol:Cell Physiol. 1984; 16:C61–C73 [DOI] [PubMed] [Google Scholar]

[bibr37-1535370219867269] 37.Riederer BM, Zagon IS, Goodman SR. Brain spectrin (240/235) and brain spectrin (240/235E): two distinct spectrin subtypes with different locations within mammalian neural cells. J. Cell Biol. 1986; 102:2088–2096 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr38-1535370219867269] 38.Goodman SR, Riederer BM, Zagon IS. Spectrin subtypes in mammalian brain. BioEssays 1986; 5:25–29 [DOI] [PubMed] [Google Scholar]

[bibr39-1535370219867269] 39.Goodman SR, Zagon IS, Riederer BM. Spectrin isoforms in mammalian brain. Brain Res. Bull. 1987; 18:787–792 [DOI] [PubMed] [Google Scholar]

[bibr40-1535370219867269] 40.Goodman SR, Zagon IS. The neural cell spectrin skeleton: A review. Am. J. Physiol: Cell Physiol 1986; 250:C347–C360 [DOI] [PubMed] [Google Scholar]

[bibr41-1535370219867269] 41.Goodman SR, Zagon IS. Brain spectrin: structure, location and function, a symposium overview. Brain Res. Bull. 1987; 18:773–776 [Google Scholar]

[bibr42-1535370219867269] 42.Riederer BM, Lopresti LL, Krebs KE, Zagon IS, Goodman SR. Brain spectrin (240/235) and brain spectrin (240/235E): Conservation of structure and location within mammalian neural tissue. Brain Res. Bull. 1988; 21:607–616 [DOI] [PubMed] [Google Scholar]

[bibr43-1535370219867269] 43.Zagon IS, Goodman SR. Absence of brain spectrin (240/235) in dendrites of mammalian brain. Brain Res. Bull. 1989; 23:19–24 [DOI] [PubMed] [Google Scholar]

[bibr44-1535370219867269] 44.Riederer BM, Zagon IS, Goodman SR. Brain spectrin (240/235) and brain spectrin (240/235E): differential expression during mouse brain development. J. Neurosci. 1987; 7:864–874 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr45-1535370219867269] 45.Zagon IS, Riederer BM, Goodman SR. Spectrin expression during mammalian brain ontogeny. Brain Res Bull 1987; 18:799–807 [DOI] [PubMed] [Google Scholar]

[bibr46-1535370219867269] 46.Zimmer WE, Ma Y, Zagon IS, Goodman SR. Developmental Expression of Brain β-Spectrin Isoform Messenger RNAs. Brain Res. Bull. 1992; 594:75–83 [DOI] [PubMed] [Google Scholar]

[bibr47-1535370219867269] 47.Levine J, Willard M. Fodrin: axonally transported polypeptides associated with the internal periphery of many cells. J. Cell Biol. 1981, 90(3) 631–642 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr48-1535370219867269] 48.Zimmer WE, Ma Y, Goodman SR. Tissue Distribution of Brain β-spectrin mRNAs. Brain Res. Bull. 1991; 27:187–193 [DOI] [PubMed] [Google Scholar]

[bibr49-1535370219867269] 49.Goodman SR, Zimmer WE, Clark MB, Zagon IS, Barker JE, Bloom ML. Brain spectrin: of mice and men. Brain Res. Bull. 1995; 36:593–606 [DOI] [PubMed] [Google Scholar]

[bibr50-1535370219867269] 50.Clark MB, Ma Y, Bloom M, Barker J, Zagon IS, Zimmer WE, Goodman SR. Brain α Erythroid Spectrin: Identification, compartmentalization, and β- Spectrin Associations. Brain Res. Bull. 1994; 663:223–226 [DOI] [PubMed] [Google Scholar]

[bibr51-1535370219867269] 51.Morrow JS, Marchesi VT. Self-assembly of spectrin oligomers in vitro: A basis for a dynamic cytoskeleton. J. Cell Biol. 1981; 88(2): 463–468 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr52-1535370219867269] 52.Speicher DW, Davis G, Marchesi VT. Structure of Human Erythrocyte Spectrin, II. The Sequence of the a-I Domain. J. Biol. Chem. 1983; 258: 14938–14947 [PubMed] [Google Scholar]

[bibr53-1535370219867269] 53.Yan Y, Winograd E, Viel A, Cronin T, Harrison SC, Branton D. Crystal Structure of the repetitive segments of spectrin, Science 1993, 252: 2027–2030 [DOI] [PubMed] [Google Scholar]

[bibr54-1535370219867269] 54.Grum VL, Li D, MacDonald RI, Mondragon A, Structures of Two Repeats of Spectrin Suggest Models of Flexibility. Cell 1999, 98, 523–535 [DOI] [PubMed] [Google Scholar]

[bibr55-1535370219867269] 55.Ipsaro JJ, Harper SL, Messick TE, Marmorstein R, Mondragón A, Speicher DW. Crystal structure and functional interpretation of the erythrocyte spectrin tetramerization domain complex. Blood 2010, 115: 4843–4852 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr56-1535370219867269] 56.Takeuchi M, Miyamoto H, Sako Y, Komizu H, Kusumi A. Structure of the erythrocyte membrane skeleton as observed by atomic force microscopy. Biophys. J. 1998; 74: 2171–2183 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr57-1535370219867269] 57.Swihart AH, Mikrut JM, Ketterson JB, Macdonald RC. Atomic force microscopy of the erythrocyte membrane skeleton. J Microsc. 2001; 204(3):212–225 [DOI] [PubMed] [Google Scholar]

[bibr58-1535370219867269] 58.Brown JW, Bullitt E, Sriswasdi S, Harper S, Speicher DW, McKnight CJ. The physiological molecular shape of spectrin: a compact supercoil resembling a Chinese finger Trap. PLOS Comput Biol 2015; 11:e1004302. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr59-1535370219867269] 59.Sahr KE, Laurila P, Kotula L, Scarpa AL, Coupal E, Leto TL, Linnenbach A.J., Winkelmann J.C., Speicher D.W., Marchesi V.T., Curtis P.J., Forget B.G. The complete cDNA and polypeptide sequences of human erythroid alpha-spectrin. J. Biol. Chem. 1990; 265(8):4434–4443 [PubMed] [Google Scholar]

[bibr60-1535370219867269] 60.Cioe L, Laurila P, Pacifico M, Krebs K, Goodman SR, Curtis PJ. Cloning and nucleotide sequence of a mouse erythrocyte-β spectrin cDNA. Blood 1987; 70(4):915–920 [PubMed] [Google Scholar]

[bibr61-1535370219867269] 61.Winkelmann JC, Chang JG, Tse WT, Scarpa AL, Marchesi VT, Forget BG. Full-length sequence of the cDNA for human erythroid beta-spectrin. J. Biol. Chem. 1990; 265(20):11827–32 [PubMed] [Google Scholar]

[bibr62-1535370219867269] 62.Moon RT., McMahon AP. Generation of diversity in nonerythroid spectrins. Multiple polypeptides are predicted by sequence analysis of cDNAs encompassing the coding region of human nonerythroid alpha-spectrin. J. Biol. Chem. 1990; J. Biol. Chem. 265:4427-4433:4427–4433 [PubMed] [Google Scholar]

[bibr63-1535370219867269] 63.Hu RJ., Watanabe M., Bennett V. Characterization of human brain cDNA encoding the general isoform of beta-spectrin. J. Biol. Chem. 1992; 267:18715–18722 [PubMed] [Google Scholar]

[bibr64-1535370219867269] 64.Ma Y, Zimmer WE, Riederer BM, Bloom ML, Barker JE, Goodman SR. The Complete Amino Acid Sequence for Brain β Spectrin (β fodrin): Relationship to Globin Sequences. Mol. Brain Res. 1993; 18:87–99 [DOI] [PubMed] [Google Scholar]

[bibr65-1535370219867269] 65.Winkelmann JC, Forget BG. Erythroid and nonerythroid spectrins. Blood 1993; 81:3173–3185 [PubMed] [Google Scholar]

[bibr66-1535370219867269] 66.Trave G, Lacombe P-J, Pfuhl M, Saraste M, Pastore A. Molecular mechanism of the calcium-induced conformational change in the spectrin EF-hands. EMBO Journal 1995; 14: 4922–4931 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr67-1535370219867269] 67.Musacchio A, Noble M, Pauptit R, Wierenga R, Saraste M. Crystal structure of a Src-homology 3 (SH3) domain. Nature 1992; 359: 851–855 [DOI] [PubMed] [Google Scholar]

[bibr68-1535370219867269] 68.Fen S, Chen JK, Yu H, Simon JA, Schreiber SL. Two binding orientations for peptides to the Src SH3 domain: development of a general model for SH3-ligand interactions. Science 1994; 266:1241–1247 [DOI] [PubMed] [Google Scholar]

[bibr69-1535370219867269] 69.Mayer BJ. SH3 domains: complexity in moderation. J Cell Sci 2001; 114:1253–1263 [DOI] [PubMed] [Google Scholar]

[bibr70-1535370219867269] 70.Chang TC, Cubillos FF, Kakhniashvili DG, Goodman SR. Band 3 is a Target of Spectrin’s E2/E3 Activity: Implications for Sickle Cell Disease and Normal RBC Aging. Cell. and Molec. Biol. 2004; 50:171–177 [PubMed] [Google Scholar]

[bibr71-1535370219867269] 71.Chang TL, Cubillos FF, Kakhniashvili DG, Goodman SR. Ankyrin is a target of spectrin’s E2/E3 ubiquitin-conjugating/ligating activity. Cell. and Molec. Biol. 2004; 50:59–66 [PubMed] [Google Scholar]

[bibr72-1535370219867269] 72.Macias MJ, Musachhhio A, Ponstingl H, Nilges M, Saraste M, Oschkinat H. Structure of the pleckstrin homology domain from beta-spectrin. Nature 1994; 369: 675–677 [DOI] [PubMed] [Google Scholar]

[bibr73-1535370219867269] 73.Karinch AM, Zimmer WE, Goodman SR. The Identification and Sequence of the Actin-Binding Domain of Human Red Blood Cell β-Spectrin. J. Biol. Chem. 1990; 265:11833–11840 [PubMed] [Google Scholar]

[bibr74-1535370219867269] 74.Hartwig JH. Actin-binding proteins. 1. Spectrin super family, Protein Profile 1995; 2: 703–800 [PubMed] [Google Scholar]

[bibr75-1535370219867269] 75.Castresana J, Saraste M, Does Vav bind to F-actin through a CH domain? FEBS Lett. 1995; 374: 149–151 [DOI] [PubMed] [Google Scholar]

[bibr76-1535370219867269] 76.Djinovic Carugo K, Banuelos S, Saraste M, Crystal structure of a calponin homology domain, Nat. Struct. Biol. 1997; 4: 175–179 [DOI] [PubMed] [Google Scholar]

[bibr77-1535370219867269] 77.Banuelos S, Saraste M, Djinovic Carugo K, Structural comparisons of calponin homology domains: implications for actin binding. Structure 1998; 6: 1419–1431 [DOI] [PubMed] [Google Scholar]

[bibr78-1535370219867269] 78.Harris AS, Morrow JS, Proteolytic processing of human brain alpha spectrin (fodrin): identification of a hypersensitive site, J. Neurosci. 1988; 8: 2640–2651 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr79-1535370219867269] 79.Harris AS, Croall DE, Morrow JS. Calmodulin regulates fodrin susceptibility to cleavage by calcium-dependent protease I. J Biol Chem 1989; 264:17401–17408 [PubMed] [Google Scholar]

[bibr80-1535370219867269] 80.Nicolas G, Fournier CM, Galand C, Malbert-Colas L, Bournier O, Kroviarski Y, Bourgeois M, Camonis JH, Dhermy D, Grandchamp B, Lecomte MC. Tyrosine phosphorylation regulates alpha II spectrin cleavage by calpain. Mol Cell Biol 2002; 22:3527–3536 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr81-1535370219867269] 81.Nedrelow JH, Cianci CD, Morrow JS, C-Src binds αII spectrin’s Src homology 3 (SH3) domain and blocks calpain susceptibility by phosphorylating Tyr1176. J Biol Chem 2003; 278:7725–7741 [DOI] [PubMed] [Google Scholar]

[bibr82-1535370219867269] 82.Rotter B, Kroviarski Y, Nicolas G, Dhermy D, Lecomte MC. AlphaII-spectrin is an in vitro target for caspase-2, and its cleavage is regulated by calmodulin binding, Biochem. J. 2004; 378: 161–168 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr83-1535370219867269] 83.Glantz S.B., Cianci C.D., Iyer R., Pradhan D., Wang K.K., Morrow J.S., Sequential degradation of alphaII and betaII spectrin by calpain in glutamate or maitotoxin-stimulated cells, Biochemistry 2007; 46:502–513 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr84-1535370219867269] 84.Fabregat A, Jupe S, Matthews L, Sidiroppoulos K, Gillespie M, Garapati P, Haw R, Jassal B, Korninger F, May B, Milacic M, Roca CD, Rothfels K, Sevilla C, Shamovsky V, Shorser S, Varusai T, Viteri G, Weiser J, Wu G, Stein L, Hermjakob H, D’Eustachio P. The Reactome Pathway Knowledgebase. Nucleic Acid Research 2019; 46(D1):D649–D655 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr85-1535370219867269] 85.Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015; 1(6):417–425 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr86-1535370219867269] 86.Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, von Mering C. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019; 47:D607–613. https://string-db.org/ [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr87-1535370219867269] 87.Thul PJ, et al. A subcellular map of the human proteome. Science 2017;356:820 [DOI] [PubMed]

[bibr88-1535370219867269] 88.Corsi D, Galluzzi L, Crinelli R, Magnani M. Ubiquitin is conjugated to the cytoskeletal protein alpha-spectrin in mature erythrocytes. J. Biol. Chem.1995; 270(15):8928–8935 [DOI] [PubMed] [Google Scholar]

[bibr89-1535370219867269] 89.Galluzi L, Nicholas G, Paiardini M, Magnani M, Lecomte MC. Identification of ubiquitinated repeats in human erythroid α-spectrin. Eur J Biochem 2000; 267:2812–2818 [DOI] [PubMed] [Google Scholar]

[bibr90-1535370219867269] 90.Galluzzi L, Paiardini M, Lecomte MC, Magnani M. Identification of the main ubiquitination site in human erythroid alpha-spectrin. FEBS Lett. 2001; 489(2-3):254–258 [DOI] [PubMed] [Google Scholar]

[bibr91-1535370219867269] 91.Sangerman J, Killilea AS, Chronister R, Pappolla MA, Goodman SR. α Spectrins are Major Ubiquitinated Proteins in Hippocampal Neurons and Components of Ubiquitinated Inclusions in Neurodegenerative Disorders. Brain Res. Bull. 2001; 54:405–511 [DOI] [PubMed] [Google Scholar]

[bibr92-1535370219867269] 92.Sangerman J, Kakhniashvili D, Brown A, Shartava A, Goodman SR. Spectrin Ubiquitination and Oxidative Stress: Potential Roles in Blood and Neurological Disorders. Cell Biol. Lett. 2001; 6:607–636 [PubMed] [Google Scholar]

[bibr93-1535370219867269] 93.Bennett V, Davis J. Erythrocyte ankyrin: Immunoreactive analogues are associated with mitotic structures in cultured cells and with microtubules in brain. Proc. Natl. Acad. Sci. USA. 1981; 78: 7550–7554 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr94-1535370219867269] 94.Bennett V, Healy J. Membrane Domains Based on Ankyrin and Spectrin Associated with Cell–Cell Interactions. Cold Spring Harbor Persp. in Biol. 2009; 1: a003012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr95-1535370219867269] 95.Goodman SR, Casoria LA, Coleman DB, Zagon IS. Identification and location of Brain protein 4.1. Science 1984; 224:1433–1436 [DOI] [PubMed] [Google Scholar]

[bibr96-1535370219867269] 96.Krebs KE, Zagon IS, Goodman SR. Amelin: A 4.1-related spectrin binding protein found in neuronal cell bodies and dendrites. J. Neurosci. 1987; 7(12):3907–3914 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr97-1535370219867269] 97.Zimmer WE, Zagon IS, Casoria LA, Goodman SR. Identification of an Amelin Isoform Located in Axons. Brain Res. Bull. 1992; 582:94–100 [DOI] [PubMed] [Google Scholar]

[bibr98-1535370219867269] 98.Krebs KE, Zagon IS, Sihag RK, Goodman SR. Brain protein 4.1 subtypes: A working hypothesis. BioEssays 1987; 6:274–279 [DOI] [PubMed] [Google Scholar]

[bibr99-1535370219867269] 99.Baines A J., Lu H -C, Bennett P M. The protein 4.1 family: Hub proteins in animals for organizing membrane proteins. Biochim. Biophys. Acta - Biomembranes, 2014; 1838, 605–619 [DOI] [PubMed] [Google Scholar]

[bibr100-1535370219867269] 100.Wu S, Sangerman J, Li M, Brough GH, Goodman SR, Stevens T. Essential Control of an endothelial cell Isoc by the spectrin membrane skeleton. J. Cell Biol. 2001; 154:1–1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr101-1535370219867269] 101.Wu S, Cioffi E, Alvarez D, Sayner S, Chen H, Cioffi D, King J, Creighton J, Townsley M, Goodman SR, Stevens T. Essential Role of a Ca²⁺ Selective, Store Operated Current (ISOC) in Endothelial Cell Permeability. Determination of the Vascular Leak Site. Circul. Res. 2005; 96:856–863 [DOI] [PubMed] [Google Scholar]

[bibr102-1535370219867269] 102.Cioffi DL, Wu S, Alexeyev M, Goodman SR, Zhu MX, Stevens T. Activation of the Endothelial Store-Operated/_socCa²⁺ Channel Requires Activation of Protein 4.1 with TRPC4. Circ. Res. 2005; 197:1164–1170 [DOI] [PubMed] [Google Scholar]

[bibr103-1535370219867269] 103.Davis L, Abdi K, Machius M, Brautigam C, Tomchick DR, Bennett V, Michaely P. Localization and structure of the ankyrin-binding site on β2-spectrin. J Biol Chem 2008; 284: 6982–6987 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr104-1535370219867269] 104.Ipsaro JJ, Huang L, Mondragon A. Structures of the spectrin-ankyrin interaction binding domains. Blood 2009; Blood 113: 5385–5393 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr105-1535370219867269] 105.Stabach PR, Simonović I, Ranieri MA, Aboodi MS, Steitz TA, Simonović M, Morrow JS. 2009. The structure of the ankyrin-binding site of β-spectrin reveals how tandem spectrin-repeats generate unique ligand-binding properties. Blood 113: 5377–5384 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr106-1535370219867269] 106.An X., Debnath G., Guo X., Liu S., Lux S.E., Baines A., Gratzer W., Mohandas N., Identification and functional characterization of protein 4.1R and actin-binding sites in erythrocyte beta spectrin: regulation of the interactions by phosphatidylinositol-4,5-bisphosphate, Biochemistry 2005; 44: 10681–10688 [DOI] [PubMed] [Google Scholar]

[bibr107-1535370219867269] 107.Zimmer WE, Zhao Y, Sikorski AF, Critz S, Sangerman J, Elferink L, Xu XS, Goodman SR. The Domain of β-Spectrin Responsible for Synaptic Vesicle Association is Essential for Synaptic Transmission. Brain Res. 2000; 881:18–27 [DOI] [PubMed] [Google Scholar]

[bibr108-1535370219867269] 108.Krebs KE, Prouty SM, Zagon IS, Goodman SR. The structural and functional relationship of RBC protein 4.1 to synapsin I. Am. J. Physiol. Cell Physiol. 1987; 22:C500–C505 [DOI] [PubMed] [Google Scholar]

[bibr109-1535370219867269] 109.Goodman SR, Kurdia A, Ammann L, Kakhniashvili D, Daescu O. The Human Red Blood Cell Proteome and Interactome. Exp. Biol. & Med. 2007; 232:1391–1408 [DOI] [PubMed] [Google Scholar]

[bibr110-1535370219867269] 110.Goodman SR, Daescu O, Kakhniashvili D, Zivanic M. The Proteomics and Interactomics of Human Erythrocytes. Exp. Biol. & Med. 2013; 238: 509–518 [DOI] [PubMed] [Google Scholar]

[bibr111-1535370219867269] 111.Machnicka B, Czogalla A, Hryniewicz-Jankowska A, Boguslawska DM, Grochowalska R, Heger E, Sikorski AF. Spectrins: A structural platform for stabilization and activation of membrane channels, receptors and transporters. Biochim. Biophys. Acta 2014; 1838: 620–634 [DOI] [PubMed] [Google Scholar]

[bibr112-1535370219867269] 112.Unsain N, Stefani FD, Cáceres A. The Actin/Spectrin Membrane-Associated Periodic Skeleton in Neurons. Front Synaptic Neurosci. 2018; 10:10. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr113-1535370219867269] 113.Han B, Zhou R, Xia C, Zhuang X. Structural organization of the actin-spectrin-based membrane skeleton in dendrites and soma of neurons. Proc Natl Acad Sci U S A. 2017; 114(32):E6678–E6685 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr114-1535370219867269] 114.Hirokawa N, Noda Y, Tanaka Y, Niwa S. Kinesin superfamily motor proteins and intracellular transport. Nature Reviews 2009; 10: 682–696 [DOI] [PubMed] [Google Scholar]

[bibr115-1535370219867269] 115.Takeda S, Yamazaki H, Seng D-H, Kanai Y, Terada S, Hirokawa N. Kinesin Superfamily Protein 3 (KIF3) Motor Transports Fodrin-associating Vesicles Important for Neurite Building. J. Cell Biol. 2000; 148: 1255–1265 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr116-1535370219867269] 116.Beck KA, Buchanan JA, Malhotra V, Nelson WJ. Golgi spectrin: identification of an erythroid beta-spectrin homolog associated with the Golgi complex. J Cell Biol. 1994; 127(3):707–23 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr117-1535370219867269] 117.Salcedo-Sicilia L, Granell S, Jovis M, Sicart A, Mato E, Johannes L, Balla T, Egea G. βIII Spectrin Regulates the Structural Integrity and the Secretory Protein Transport of the Golgi Complex. J. Biol. Chem. 2013; 228(4):2157–2166 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr118-1535370219867269] 118.Olenick MA, Holzbaur ELF, Dynein activators and adaptors at a glance. J. Cell Sci. 2019; 132: jcs227132. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr119-1535370219867269] 119.Holleran EA, Ligon LA, Tokito M, Stankewich MC, Morrow JS, Holzbaur ELF. βIII Spectrin Binds to the Arp1 Subunit of Dynactin. J. Biol. Chem. 2001; 276(39):36598–36605 [DOI] [PubMed] [Google Scholar]

[bibr120-1535370219867269] 120.Sikorski AF, Terlecki G, Zagon IS, Goodman SR. Synapsin I- mediated Interaction of Brain Spectrin with Small Synaptic Vesicles. J. Cell Bio. 1991; 114:313–318 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr121-1535370219867269] 121.Sikorski AF, Goodman SR. The Effect of Synapsin I Phosphorylation Upon Binding of Synaptic Vesicles to Spectrin. Brain Res. Bull. 1991; 27:195–198 [DOI] [PubMed] [Google Scholar]

[bibr122-1535370219867269] 122.Sikorski A, Sangerman J, Goodman SR, Critz S. Spectrin (βSpllΣ1) is an essential component in synaptic transmission. Brain Res. 2000; 852:161–166 [DOI] [PubMed] [Google Scholar]

[bibr123-1535370219867269] 123.Goodman SR. Discovery of Nonerythroid Spectrin to the Demonstration of its Key Role in Synaptic Transmission. Brain Res. Bull; 1999; 50(5/6):345–346 [DOI] [PubMed] [Google Scholar]

[bibr124-1535370219867269] 124.Lambert MW. Spectrin and its interacting partners in nuclear structure and function. Exp. Biol. and Med. 2018; 243:507–524 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr125-1535370219867269] 125.Zagon IS, McLaughlin PJ, Goodman SR. Localization of spectrin in mammalian brain. J. Neurosci. 1984; 4:3089–3100 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr126-1535370219867269] 126.Borland K, Osawa S, Kew D, Coleman DB, Goodman SR, Hall PF. Identification of a spectrin-like protein in sertoli cells. Biol. Reprod. 1985; 32:1143–1156 [DOI] [PubMed] [Google Scholar]

[bibr127-1535370219867269] 127.Goodman SR, Zagon IS, Coleman DB, McLaughlin PJ. Spectrin expression in neuroblastoma cells. Brain Res. Bull. 1986; 16:597–602 [DOI] [PubMed] [Google Scholar]

[bibr128-1535370219867269] 128.Osawa S, Kew D, Borland K, Coleman DB, Goodman SR, Halls PF. Occurrence of spectrin-like protein in Y-1 adrenal tumor cells. Endocrinology 1986; 118:2458–2463 [DOI] [PubMed] [Google Scholar]

[bibr129-1535370219867269] 129.Isayama T, Goodman SR, Zagon IS. Spectrin Isoforms in the Mammalian Retina. J. Neurosci. 1991; 11:3531–3538 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr130-1535370219867269] 130.Isayama T, Goodman SR, Zagon IS. Localization of Spectrin Isoforms in the Adult Heart. Cell & Tissue Research 1993; 274:127–133 [DOI] [PubMed] [Google Scholar]

[bibr131-1535370219867269] 131.Kumaresan KR, Hang B, Lambert MW. Human endonucleolytic incision of DNA 3’ and 5’ to a site-directed psoralen monoadduct and interstrand cross-link. J Biol Chem 1995; 270:30709–30716 [DOI] [PubMed] [Google Scholar]

[bibr132-1535370219867269] 132.McMahon LW, Walsh CE, Lambert MW. Human α spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex. J Biol Chem 1999; 274:32904–32908 [DOI] [PubMed] [Google Scholar]

[bibr133-1535370219867269] 133.Brois DW, McMahon LW, Ramos NL, Anglin LM, Walsh CE, Lambert MW. A deficiency in a 230 kDA DNA repair protein in Fanconi anemia complementation group A cells is corrected by the FANCA cDNA. Carcinogenesis 1999; 20:1845–1853 [DOI] [PubMed] [Google Scholar]

[bibr134-1535370219867269] 134.Kumaresan KR, Lambert MW. Fanconi anemia, complementation group A, cells are defective in ability to produce incisions at sites of psoralen interstrand cross-links. Carcinogenesis 2000; 21:741–751 [DOI] [PubMed] [Google Scholar]

[bibr135-1535370219867269] 135.McMahon LW, Sangerman J, Goodman SR, Lambert MW. Human Alpha Spectrin II, in Association with the FANCA, FANCC and FANCG Proteins, Binds to DNA Containing Psoralen Interstrand Cross-links. Biochemistry 2001; 40:7025–7034 [DOI] [PubMed] [Google Scholar]

[bibr136-1535370219867269] 136.Sridharan D, Brown M, Lambert WC, McMahon LW, Lambert MW. Nonerythroid alphaII spectrin is required for recruitment of FANCA and XPF to nuclear foci induced by DNA interstrand cross-links. Journal of Cell Science 2003; 116(Pt 5):823–835 [DOI] [PubMed] [Google Scholar]

[bibr137-1535370219867269] 137.Tripsianes K, Folkers GE, Ab E, Das D, Odijk H, Jaspers NGJ, Hoeijmakers JHJ, Kapten R, Boelens R. The structure of the human ERCC1/XPF interaction domains reveals a complementary role for the two proteins in nucleotide excision repair. Structure 2005; 13:1849–1858 [DOI] [PubMed] [Google Scholar]

[bibr138-1535370219867269] 138.Choi YJ, Ryu KS, Ko YM, Chae YK, Pleton JG, Wemmer DE, Choi BS. Biophysical characterization of the interaction domains and mapping of the contact residues in the XPF-ERCC1 complex. J Biol Chem 2005; 280:28644–28652 [DOI] [PubMed] [Google Scholar]

[bibr139-1535370219867269] 139.Kumaresan K, Sridharan D, McMahon L, Lambert MW. Deficiency in incisions produced by XPF at the site of a DNA interstrand cross-link in Fanconi anemia cells. Biochemistry 2007; 46:14359–14368 [DOI] [PubMed] [Google Scholar]

[bibr140-1535370219867269] 140.Lefferts JA, Wang C, Sridharan D, Baralt M, Lambert MW. The SH3 domain of alphaII spectrin is a target for the Fanconi anemia protein, FANCG. Biochemistry 2009; 48(2):254–263 [DOI] [PubMed] [Google Scholar]

[bibr141-1535370219867269] 141.McMahon LW, Zhang P, Sridharan DM, Lefferts JA, Lambert MW. Knockdown of αII spectrin in normal human cells by siRNA leads to chromosomal instability and decreased DNA interstrand cross-link repair. Biochem Biophys Res Commun 2009; 381:288–293 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr142-1535370219867269] 142.Wang C, Lambert MW. The Fanconi anemia protein, FANCG, binds to the ERCC1-XPF endonuclease via its tetratricopeptide repeats and the central domain of ERCC1. Biochemistry 2010; 49:5560–5569 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr143-1535370219867269] 143.de Winter JP, Joenje H. The genetic and molecular basis of Fanconi anemia. Mutat Res 2009; 668:11–19 [DOI] [PubMed] [Google Scholar]

[bibr144-1535370219867269] 144.Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet 2008; 42:301–334 [DOI] [PubMed] [Google Scholar]

[bibr145-1535370219867269] 145.de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 2005; 19:2100–2110 [DOI] [PubMed] [Google Scholar]

[bibr146-1535370219867269] 146.O’Sullivan RJ, Karlseder J. Telomeres: protecting chromosomes against genome instability. Nat Rev Mol Cell Biol 2010; 11:171–181 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr147-1535370219867269] 147.Zhang P, Herbig U, Coffman F, Lambert MW. Non-erythroid alpha spectrin prevents telomere dysfunction after DNA interstrand cross-link damage. Nucleic Acids Res, 2013; 41:5321–5340. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr148-1535370219867269] 148.Crisp M, Liu Q, Rous K, Rattner JB, Shanahan C, Burke B, Stahl PD, Hodzic D. Coupling of the nucleus and the cytoplasm: role of the LINC complex. J Cell Biol 2005; 172:41–53 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr149-1535370219867269] 149.Lottersberger F, Karssemeijer N, Dimitrova N, de Lange T. 53BP1 and the LINC complex promote microtubule-dependent DSB mobility and DNA repair. Cell 2015; 163:880–893 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr150-1535370219867269] 150.Lawrence KS, Tapley EC, Cruz VE, Li Q, Aung K, Hart KC, Schwartz TU, Starr DA, Engebrecht J. LINC Complexes promote homologous recombination in part through inhibition of nonhomologous end joining. J Cell Biol 2016; 215:801–821 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr151-1535370219867269] 151.Stroud MJ. Linker of nucleoskeleton and cytoskeleton complex proteins in cardiomyopathy. Biophysical Reviews 2018; 10:1033–1051 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr152-1535370219867269] 152.Haque F, Lloyd DJ, Smallwood DT, Dent CL, Shanahan CM, Fry CM, Trembath RC, Shackleton SUN1. Interacts with nuclear lamin A and cytoplasmic nesprins to provide a physical connection between the nuclear lamina and the cytoskeleton. Mol Cell Biol 2006; 26:3738–3751 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr153-1535370219867269] 153.Lombardi ML, Jaalouk DE, Shanhan MC, Burke B, Roux KJ, Lammerding J. The interaction between nesprins and Sun proteins at the nuclear envelope is critical for force transmission between the nucleus and cytoskeleton. J Biol Chem 2011; 286:26743–26753 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr154-1535370219867269] 154.Dechat T, Pfleghaar K, Sengupta K, Shimi T, Shumaker DK, Solimando L, Goldman RD. Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes Dev 2008; 22:832–853 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr155-1535370219867269] 155.Goldman RD, Gruenbaum Y, Moir RD, Shumaker DK, Spann TP. Nuclear lamins: building blocks of nuclear architecture. Gene Dev 2002; 16:533–547 [DOI] [PubMed] [Google Scholar]

[bibr156-1535370219867269] 156.Gruenbaum Y., Medalia O. Lamins: the structure and protein complexes. Curr Opin Cell Biol 2015; 32:7–12 [DOI] [PubMed] [Google Scholar]

[bibr157-1535370219867269] 157.Bengtsson L, Wilson KL. Multiple and surprising new functions for emerin, a nuclear membrane protein. Curr Opin Cell Biol 2004; 16:73–79 [DOI] [PubMed] [Google Scholar]

[bibr158-1535370219867269] 158.Berk JM, Tifft KE, Wilson KL. The nuclear envelope LEM-domain protein emerin. Nucleus 2013; 4:1–17 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr159-1535370219867269] 159.Holaska JM, Kowalski AM, Wilson SL. Emerin caps the pointed end of actin filaments: evidence for an actin cortical network at the inner nuclear membrane. PLoS Biol 2004; 2:1354–1362 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr160-1535370219867269] 160.Sridharan DM, McMahon LW, Lambert MW. Alpha II-Spectrin interacts with five groups of functionally important proteins in the nucleus. Cell Biol. Internat. 2006; 30(11):866–878 [DOI] [PubMed] [Google Scholar]

[bibr161-1535370219867269] 161.Holaska JM, Wilson KL. An emerin ‘proteome’: purification of distinct emerin-containing complexes from HeLa cells suggests molecular basis for diverse roles including gene regulation, mRNA splicing, signalling, mechano-sensing and nuclear architecture. Biochemistry 2007; 46:8897–8908 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr162-1535370219867269] 162.Gerace L, Huber MD. Nuclear lamina at the crossroads of the cytoplasm and nucleus. J Struct Biol 2012; 177:24–31 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr163-1535370219867269] 163.Lammerding J, Schulze PC, Takahaski T, Kozlov S, Sullivan T, Kamm RD, Stewart CL, Lee RT. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Invest 2004; 113:370–378 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr164-1535370219867269] 164.Lammerding J, Hsiao J, Schulze PC, Kazlov S, Stewart CL, Lee RT. Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells. J Cell Biol 2005; 170:781–791 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr165-1535370219867269] 165.Dahl KN, Riberio AJS, Lammerding J. Nuclear shape, mechanics and mechanotransduction. Circ Res 2008; 102:1307–1318 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr166-1535370219867269] 166.Dhal KN, Kalinowski A. Nucleoskeleton mechanics at a glance. J Cell Sci 2011; 124:675–678 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr167-1535370219867269] 167.Martins RP, Finan JD, Guilak F, Lee DA. Mechanical regulation of nuclear structure and function. Annu Rev Biomed Eng 2012; 14:431–455 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr168-1535370219867269] 168.Armiger TJ, Spagnol ST, Dahl KN. Nuclear mechanical resilience but not stiffness is modulated by αII-spectrin. J Biomech 2016; 49:3983–3989 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr169-1535370219867269] 169.Zhang Y, Alexander PB, Wang XF. TGF-β Family Signaling in the Control of Cell Proliferation and Survival. Cold Spring Harb. Perspect. Biol. 2017;; 9(4): pii: a022145. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr170-1535370219867269] 170.Machnicka B, Grochowalska R, Boguslawska DM, Sikorski AF, Lecomte MC. Spectrin-based skeleton as an actor in cell signaling. Cell Mol Life Sci 2012; 69:191–201 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr171-1535370219867269] 171.Thenappan A, Shukkla V, Abdul Khalek FJ, Li Y, Shetty K, Liu P, Li L, Johnson RL, Johnson L, Mishra L. Loss of TGFβ adaptor protein β2SP leads to delayed liver regeneration in mice. Hepatology 2011; 53:1641–1650 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr172-1535370219867269] 172.Metral S, Machnicka B, Bigot S, Colin Y, Dhermy D, Lecomte M-C. αII-Spectrin is critical for cell adhesion and cell cycle. J Biol Chem 2009; 284:2409–2418 [DOI] [PubMed] [Google Scholar]

[bibr173-1535370219867269] 173.Pollerberg GE, Schachner M, Davoust J. Differentiation state dependent surface mobilities of two forms of the neural cell adhesion molecule. Nature 1986; 324:462–465 [DOI] [PubMed] [Google Scholar]

[bibr174-1535370219867269] 174.Pollerberg GE, Burridge K, Krebs KE, Goodman SR, Schachner M. The 180 kD component of the neural cell adhesion molecule N-CAM is involved in cell-cell contacts and cytoskeleton-membrane interactions. Cell and Tissue Res. 1987; 250:227–236 [DOI] [PubMed] [Google Scholar]

[bibr175-1535370219867269] 175.Sytnyk V, Leshchyns’ka I, Schachner M. Neural Cell Adhesion Molecules of the Immunoglobulin Superfamily Regulate Synapse Formation, Maintenance, and Function. Trends in Neurosci. 2017; 40(5):295–308 [DOI] [PubMed] [Google Scholar]

[bibr176-1535370219867269] 176.Sytnyk V, Leshchyns’ka I, Nikonenko AG, Schachner M. NCAM promotes assembly and activity-dependent remodeling of the postsynaptic signaling complex. J. Cell Biol. 2006; 174:1071–1085 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr177-1535370219867269] 177.Chang TL, Kakhniashvili DG, Goodman SR. Spectrin’s E2/E3 Ubiquitin Conjugating/Ligating Activity is Diminished in Sickle Cells. Am. J. Hematol. 2005; 79:89–96 [DOI] [PubMed] [Google Scholar]

[bibr178-1535370219867269] 178.Ohta S, Shiomi Y, Sugimoto K, Obuse C, Tsurimoto T. A Proteomics Approach to Identify Proliferating Cell Nuclear Antigen (PCNA)-binding Proteins in Human Cell Lysates. J. Biol. Chem. 2002; 277(43):40362–40368 [DOI] [PubMed] [Google Scholar]

[bibr179-1535370219867269] 179.Srivastava M, Chen Z, Zhang H, Tang M, Wang C, Jung SY, Chen J. Replisome Dynamics and Their Functional Relevance upon DNA Damage through the PCNA Interactome. Cell Reports 2018; 25:3869–3883 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr180-1535370219867269] 180.Monteiro CA, Gibson XA, Shartava A, Goodman SR. Preliminary Characterization of a Structural Defect in Homozygous Sickled Cell Alpha Spectrin Demonstrated By A Rabbit Autoantibody. Am. J. Hematol. 1998; 58:200–205 [DOI] [PubMed] [Google Scholar]

[bibr181-1535370219867269] 181.Gibson XA, Shartava A, McIntyre J, Monteiro CA, Zhang Y, Shah A, Campbell N, Goodman SR. The Efficacy of Reducing Agents or Antioxidants in Blocking the Formation of Irreversibly Sickled Cells In Vitro. Blood 1998; 91(11):4373–4378 [PubMed] [Google Scholar]

[bibr182-1535370219867269] 182.Goodman SR, Pace BS, Shartava A. New Therapeutic Approaches to Sickle Cell Disease: Targeting RBC Membrane Oxidative Damage. Cell Mol. Biol. Lett. 1999; 3:403–411 [Google Scholar]

[bibr183-1535370219867269] 183.Goodman SR. The Role of the Membrane Skeleton in Formation of the Irreversibly Sickle Cell: A Review. Cell. & Mol. Biol. Lett. 1996; 1:105–112 [Google Scholar]

[bibr184-1535370219867269] 184.Shartava A, Shah AK, Goodman SR. N-acetylcysteine and Clotrimazole Inhibit Sickle Erythrocyte Dehydration Induced by 1-Chloro – 2,4-Dinitrobenzene. Am. J. Hemat. 1999; 62:19–24 [DOI] [PubMed] [Google Scholar]

[bibr185-1535370219867269] 185.Shartava A, McIntyre J, Shah AK, Goodman SR. The Gardos Channel is Responsible for CDNB Induced Dense Sickle Cell Formation. Amer. J. Hematol. 2000; 64(3):184–189 [DOI] [PubMed] [Google Scholar]

[bibr186-1535370219867269] 186.Pace BS, Shartava A, Pack-Mabien A, Mulekar M, Ardia A, Goodman SR. Effects of N-Acetylcysteine on Vaso-occlusive Episodes in Sickle Cell Disease. Am. J. Hematol. 2003; 73:26–32 [DOI] [PubMed] [Google Scholar]

[bibr187-1535370219867269] 187.Goodman SR, Pace BS, Daescu O, Hansen KC, D’Alessandro A, Yang X, Glatt SJ. Multiomic Candidate Biomarkers For Clinical Manifestations Of Sickle Cell Severity: Acquiring Validated Biomarkers For Precision Medicine. Exp. Biol. & Med. 2016; 241:772–781 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr188-1535370219867269] 188.Riahi MH, Kakhniashvili DG, Goodman SR. Ubiquitination of Red Blood Cell α-Spectrin Does Not Effect Heterodimer Formation. Am. J. Hematol. 2005; 78:281–287 [DOI] [PubMed] [Google Scholar]

[bibr189-1535370219867269] 189.Ghatpande SG, Goodman SR. Ubiquitination of spectrin regulates the erythrocyte spectrin-protein 4.1-actin ternary complex dissociation: implications for sickle cell membrane skeleton. Cell Mol Biol 2004; 50:67–74 [PubMed] [Google Scholar]

[bibr190-1535370219867269] 190.Mishra R, Goodman SR. Ubiquitination of Spectrin Regulates the Dissociation of the Spectrin-Adducin-F-Actin Ternary Complex In Vitro. Cell Mol. Biol. 2004; 50:75–80 [PubMed] [Google Scholar]

[bibr191-1535370219867269] 191.Shartava A, Monteiro CA, Bencsath FA, Schneider K, Chait BT, Gussio R, Casoria- Scott LA, Shah AK, Heuerman CA, Goodman SR. A Posttranslational Modification of β-Actin Contributes to the Slow Dissociation of the Spectrin-Protein 4.1-Actin Complex of Irreversibly Sickled Cells. J. Cell Biol. 1995; 128:805–815 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr192-1535370219867269] 192.Bencsath FA, Shartava A, Monteiro CA, Goodman SR. Identification of the β-Actin Disulfide-Linked Peptide Which Leads to the Slow Dissociation of the Irreversibly Sickled Membrane Skeleton. Biochemistry 1996; 35:4403–4408 [DOI] [PubMed] [Google Scholar]

[bibr193-1535370219867269] 193.Shartava A, Korn W, Shah AK, Goodman SR. Irreversibly Sickled Cell β-Actin: Defective Filament Formation. Am. J. Hematol.1997; 55:97–103 [DOI] [PubMed] [Google Scholar]

[bibr194-1535370219867269] 194.Abraham A, Bencsath FA, Shartava A, Kakhniashvili DG, Goodman SR. Preparation of irreversibly sickled cell β-actin from normal red blood cell β-actin. Biochemistry 2002; 41:292–296 [DOI] [PubMed] [Google Scholar]

[bibr195-1535370219867269] 195.Shartava A, Miranda P, Shah A, Montiero CA, Goodman SR. High Density Sickle Cell Erythrocyte Core Membrane Skeletons Demonstrate Slow Temperature Dependent Dissociation. Am. J. Hematol. 1996; 51:215–220 [DOI] [PubMed] [Google Scholar]

[bibr196-1535370219867269] 196.Caprio K, Condon MR, Deitch EA, Xu DZ, Feketova E, Machiedo GW. Alteration of alpha-spectrin ubiquitination after hemorrhagic shock. Amer. J. of Surgery 2008; 196(5):663–669 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr197-1535370219867269] 197.Huh GY, Glant SB, Je S, Morrow JS, Kim JH. Calpain proteolysis of αII-spectrin in the normal adult human brain. Neurosci Lett 2001; 316:41–44 [DOI] [PubMed] [Google Scholar]

[bibr198-1535370219867269] 198.Pike BR, Flint J, Dutta S, Johnson E, Wang KKW, Hayes RL. Accumulation of non-erythroid αII-spectrin and calpain-cleaved αII-spectrin breakdown products in cerebrospinal fluid after traumatic brain injury in rats. J Neurochem. 1997; 78:1297–1306 [DOI] [PubMed] [Google Scholar]

[bibr199-1535370219867269] 199.Czogalla A, Sikorski AF. Spectrin and calpain: a ‘target’ and ‘sniper’ in the pathology of neuronal cells. Cell Mol. Life Sci. 2001; 62:1913–1924 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr200-1535370219867269] 200.Rotter B, Kroviarski Y, Nicholas G, Dhermy D, Lecomte MC. AlphaII-spectrin is an in vitro target for caspase-2, and its cleavage is regulated by calmodulin binding. Biochem J 2004; 378:161–168 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr201-1535370219867269] 201.Baines AJ, Pinder JC. The spectrin-associated cytoskeleton in mammalian heart. Frontiers in Bioscience: a Journal and Virtual Library 2005; 10:3020–3033 [DOI] [PubMed] [Google Scholar]

[bibr202-1535370219867269] 202.Bennett V, Healy J. Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin. Trends Mol. Med. 2007; 14: 28–36 [DOI] [PubMed] [Google Scholar]

[bibr203-1535370219867269] 203.Cunha SR, Mohler PJ. Ankyrin protein networks in membrane formation and stabilization. J Cell Mol Med. 2009; 13:4364–76 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr204-1535370219867269] 204.Zhang R, Zhang CY, Zhao Q, Li DH. Spectrin: Structure, function and disease. Science China: Life Sciences 2013; 56(12):1076–1085 [DOI] [PubMed] [Google Scholar]

[bibr205-1535370219867269] 205.Derbala M, Guo AS, Mohler PJ, Smith SA. The role of βII spectrin in cardiac health and disease. Life Sci 2018; 192:278–285 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr206-1535370219867269] 206.Delaunay J, Dhermy D. Mutations involving the spectrin heterodimer contact site: Clinical expression and alterations in specific function. 1993; Semin. Hematol. 30(1):21–33 [PubMed] [Google Scholar]

[bibr207-1535370219867269] 207.Gallagher PG. Abnormalities of the erythrocyte membrane. Pediatr Clin North Am. 2013. Dec; 60(6):1349–1362 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr208-1535370219867269] 208.Sriswasdi S, Harper SL, Tang H.-, Gallagher PG, Speicher DW. Probing large conformational rearrangements in wild-type and mutant spectrin using structural mass spectrometry. Proc. Natl. Acad. Sci. U S A. 2014; 111(5):1801–1806 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr209-1535370219867269] 209.He B, -J, Liao L, Deng Z, -F, Tao Y, -F, Xu Y, -C, Lin F, -Q. Molecular Genetic Mechanisms of Hereditary Spherocytosis: Current Perspectives. Acta Haematol. 2018; 139:60–66 [DOI] [PubMed] [Google Scholar]

[bibr210-1535370219867269] 210.Goodman SR, Shiffer KA, Casoria LA, Eyster ME. Identification of the molecular defect in the erythrocyte membrane skeleton of some kindreds with hereditary spherocytosis. Blood 1982; 60:772–784 [PubMed] [Google Scholar]

[bibr211-1535370219867269] 211.Becker PS, Morrow JS, Lux SE. Abnormal oxidant sensitivity and beta-chain structure of spectrin in hereditary spherocytosis associated with defective spectrin-protein 4.1 binding. J Clin. Invest. 1987; 80:557–565 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr212-1535370219867269] 212.Alter BP. Cancer in Fanconi anemia, 1927-2001. Cancer 2003; 97:425–440 [DOI] [PubMed] [Google Scholar]

[bibr213-1535370219867269] 213.Mathew CG. Fanconi anaemia genes and susceptibility to cancer. Oncogene 2006; 25:5875–5884 [DOI] [PubMed] [Google Scholar]

[bibr214-1535370219867269] 214.Kim H, D’andrea AD. Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway. Genes Dev 2012; 26:1393–1408 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr215-1535370219867269] 215.Brosh RM, Jr, Bellani M, Liu Y, Seidman MN. Fanconi anemia: a DNA repair disorder characterized by accelerated decline of the hematopoietic system cell compartment and other features of aging. Ageing Res Rev 2017; 33:67–75 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr216-1535370219867269] 216.Mamrak NE, Shimamura A, Howlell NG. Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia. Blood Rev 2017; 31:93–99 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr217-1535370219867269] 217.Ackermann A, Brieger A. The role of Nonerythroid Spectrin αII in Cancer. Journal of Oncology 2019; Article ID 7079604, 14 pages [DOI] [PMC free article] [PubMed]

[bibr218-1535370219867269] 218.Gorman EB, Chen L, Albanese J, Ratech H. Pattern of spectrin expression in B-cell lymphomas: loss of spectrin isoforms is associated with nodule-forming and germinal center-related lymphomas. Mod Pathol 2007; 20:1245–1252 [DOI] [PubMed] [Google Scholar]

[bibr219-1535370219867269] 219.Wang Y, TJ, Nelson AD, Glanowska K, Murphy GC, Jenkins PM, Parent JM. Critical roles of αII spectrin in brain development and epileptic encephalopathy. J Clin. Invest. 2018; 128:760–773 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr220-1535370219867269] 220.Syrbe S, Harms FL, Parrini E, Montomoli M, Mutze U, Helbig KL, Polster T, Albrecht B, Bernbeck U, van Binsbergen E, Biskup S, Burglen L, Denecke J, Heron B, Heyne HO, Hoffmann GF, Hornemann F, Matsushige T, Matsuura R, Kato M, Korenke GC, Kuechler A, Lammer C, Merkenschlager A, Mignot C, Ruf S, Nakashima M, Saitsu H, Stamberger H, Pisano T, Tohyama J, Weckhuysen S, Werckx W, Wickeart J, Mari F, Verbeek NE, Moller RS, Koeleman B, Matsumoto N, Dobyns WB, Battaglia D, Lemke JR, Kutsche K, Guerrini R. Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy. Brain 2017; 140:2322–2336 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr221-1535370219867269] 221.Tohyama J, Nakashima M, Nabatame S, Gaik-Siew C, Miyata R, Rener-Primec Z, Kato M, Matsumoto N, Saitsu H. SPTAN1: encephalopathy: distinct phenotypes and genotypes. J Hum.Genet. 2015; 60:167–173 [DOI] [PubMed] [Google Scholar]

[bibr222-1535370219867269] 222.Chen J, Shukla V, Farci P, Andricovich J, Jogunoori W, Kwong LN, Katz LH, Sheety K, Rashid A, Su X, White J, Li L, Wang AY, Blechacz B, Raju GS, Davila M, Nguyen B-N, Stroehlein JR, Chen J, Kim SS, Levin H, Machida K, Tsukamoto H, Michaely P, Tzatsos A, Mishra B, Amber R, Mishra L. Loss of the transforming growth factor-β effector β2-spectrin promotes genomic instability. Hepatology 2017; 65:678–693 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr223-1535370219867269] 223.Zhi X, Lin L, Yang S, Bhuvaneshwar K, Wang H, Gusev Y, Lee MH, Kallakury B, Shivapurkar N, Cahn K, Tian X, Marshall JL, Byers SW, He AR. βII-Spectrin (SPTBN1) suppresses progression of hepatocellular carcinoma and Wnt signaling by regulation of Wnt inhibitor kallistatin. Hepatology. 2015. Feb; 61:598–612 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr224-1535370219867269] 224.Chen Y, Meng L, Shang H, Dou Q, Lu Z, Liu L, Wang Z, He X, Song Y. β2 spectrin-mediated differentiation repressed the properties of liver cancer stem cells through β-catenin. Cell Death and Disease 2018; 9:424. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr225-1535370219867269] 225.Ikeda Y, Dick KA, Weatherspoon MR, Gincel D, Armbrust KR, Dalton JC, Stevanin G, Dürr A, Zühlke C, Bürk K, Clark B, Brice A, Rothstein JD, Schut LJ, Day JW, Ranum LPW. Spectrin mutations cause spinocerebellar ataxia type 5. Nature Genetics 2006; 38(2):184–190 [DOI] [PubMed] [Google Scholar]

[bibr226-1535370219867269] 226.Wang CC, Ortiz-González XR, Yum SW, Gill SM, White A, Kelter E, Seaver LH, Lee S, Wiley G, Gaffney PM, Wierenga KJ, Rasband MN. βIV Spectrinopathies Cause Profound Intellectual Disability, Congenital Hyptonia, and Motor Axonal Neuropathy. Am. J. Human Genet. 2018; 102:1158–1168 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr227-1535370219867269] 227.Komada M, Soriano P. [Beta]IV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier. J Cell Biol. 2002; 156:337–348 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr228-1535370219867269] 228.Uemoto Y, Suzuki S, Terada N, Ohno N, Ohno S, Yamanaka S, Komada M, Specific role of the truncated bIV-spectrin S6 in sodium channel clustering at axon initial segments and nodes of Ranvier. 2007; J. Biol. Chem. 282: 6548–6555 [DOI] [PubMed] [Google Scholar]

[bibr229-1535370219867269] 229.Kopp-Scheinpflug C, Tempel BL. Decreased temporal precision of neuronal signaling as a candidate mechanism of auditory processing disorder. Hear Res. 2015; 330(Pt B):213–220 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr230-1535370219867269] 230.Liu Y, Qi J, Chen X, Tang M, Chu C, Zhu W, Li H, Tian C, Yang G, Zhong C, Zhang Y, Ni G, He S, Chai R, Zhong G. Critical role of spectrin in hearing development and deafness. Science Advances 2019; 5(4):1–9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[bibr231-1535370219867269] 231.Kosaka T, Komada M, Kosaka K. Sodium channel cluster, bIV-spectrin and ankyrinG positive ‘‘hot spots’’ on dendritic segments of parvalbumin-containing neurons and some other neurons in the mouse and rat main olfactory bulbs. Neurosci. Res. 2008; 62: 176–186 [DOI] [PubMed] [Google Scholar]

[bibr232-1535370219867269] 232.Papal S, Cortese M, Legendre K, Sorusch N, Dragavon J, Sahly I, Shorte S, Wolfrum U, Petit C, El-Amraoui A, The giant spectrin βV couples the molecular motors to phototransduction and Usher syndrome type I proteins along their trafficking route, Human Mol. Gen. 2013; 22: 3773–3788 [DOI] [PubMed] [Google Scholar]

PERMALINK

The Spectrinome: The Interactome of a Scaffold Protein Creating Nuclear and Cytoplasmic Connectivity and Function

Steven R Goodman

Daniel Johnson

Steven L Youngentob

David Kakhniashvili

Short abstract

Impact statement

Introduction

The Erythrocyte Membrane Skeleton

Figure 1.

Spectrin Isoforms

Figure 2.

Table 1.

Spectrin Structure

Figure 3.

Constructing the Spectrinome

Figure 4.

Table 2.

Table 3.

Figure 5.

Figure 6.

Table 4:

Functions within the Cytoplasm including Cytosol Facing Membrane Surfaces

Essential Nuclear Functions

Signaling From the Cell Surface to Within the Nucleus

Extracellular Cell – Cell Interactions

Why is Spectrin’s Chimeric E2-E3 Activity Important to Spectrin Isoform Functions?

Figure 7.

Spectrin and Human Disease

Table 5.

Postlude

Supplemental Material

Supplemental Material

Supplemental Material

Supplemental Material

Supplemental Material

Supplemental Material

Supplemental Material

Author Contributions

DECLARATION OF CONFLICTING INTERESTS

Funding

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases