Abstract
Fibrillin is a large evolutionarily ancient extracellular glycoprotein that assembles to form beaded microfibrils which are essential components of most extracellular matrices. Fibrillin microfibrils have specific biomechanical properties to endow animal tissues with limited elasticity, a fundamental feature of the durable function of large blood vessels, skin and lungs. They also form a template for elastin deposition and provide a platform for microfibril-elastin binding proteins to interact in elastic fibre assembly. In addition to their structural role, fibrillin microfibrils mediate cell signalling via integrin and syndecan receptors, and microfibrils sequester transforming growth factor (TGF)β family growth factors within the matrix to provide a tissue store which is critical for homeostasis and remodelling.
Introduction
Elastic fibres are essential components of all mammalian elastic tissues such as blood vessels, lung, joints and skin. The main components of elastic fibres are elastin and fibrillin, however an array of other matrix proteins are required for their correct assembly and function [1,2]. Elastic fibre proteins are critically important in the development and homeostasis of elastic tissues both in terms of their key roles in linking cells and matrix macromolecules [3] and in the extracellular regulation of TGFβ family member growth factors [4]. Fibrillin assembles to form beaded microfibrils [5] and the formation of elastic fibres requires a fibrillin microfibril scaffold for the correct deposition of elastin. Fibrillin also interacts with other elastic fibre proteins including the fibulins and latent TGFβ binding proteins to support elastic fibre assembly and function. In this review, we will describe our understanding of the function of fibrillin and fibrillin microfibrils, focusing on its structure, assembly and interaction with other elastic fibre proteins as well as their functional role in elastogenesis.
Fibrillin microfibrils
Fibrillin domain structure
The fibrillin superfamily family is composed of three fibrillin isoforms, fibrillin1–3, each encoded by a separate gene [[6], [7], [8], [9]], and the related extracellular matrix (ECM) proteins the latent transforming growth factor (TGF)β binding proteins (LTBPs)1–4 (Fig. 1). The domain structure of the fibrillin superfamily consists primarily of arrays of epidermal growth factor-like (EGF) domains interspersed with TGFβ-binding like (TB) domains and hybrid domains [6]. The three fibrillin isoforms are highly homologous to each other with differences including a proline rich region in fibrillin-1 which in fibrillin-2 is glycine rich and in fibrillin-3 is proline and glycine rich. Of the 47 EGF domains in fibrillin, 43 are calcium binding (cb) [6]. There are seven TB domains (also referred to as 8 cysteine domains) which are unique to the fibrillin superfamily. They have a globular structure [10,11] and domain TB4 contains an RGD motif which is involved in binding to α5β1 αvβ3 and αvβ6 integrins and essential for the interaction between fibrillin-1 and the cell surface [[12], [13], [14], [15]]. Hybrid domains have structural similarity to both EGF and TB domains [6,16,17] and there are two hybrid domains in fibrillin. The fibrillins have unique N- and C-termini which are both proteolytically processed by furin, essential for the assembly of fibrillin into microfibrils [[18], [19], [20]]. The processed C-terminal peptide, also known as asprosin, has been shown to be involved in glucose release from the liver [21]. The fibrillins undergo several other post translation modifications, fibrillin-1 has 14 predicted glycosylation sites and there are 12 sites in fibrillin-2 and 10 sites in fibrillin-3. Fibrillin-1 can also be phosphorylated at serine 2702 by FAM20C [22] but the function of phosphorylation has not yet been investigated.
Supramolecular organisation into microfibrils
Fibrillin microfibrils are beaded filaments with ~56 nm periodicity mainly composed of fibrillin molecules [23]. The microfibrils are polar polymers which linearly assemble through interaction between the N- and C-termini of adjacent fibrillin molecules [24]. Lateral association also occurs and is driven by homotypic interaction between the termini to form microfibrils [[25], [26], [27]]. Scanning transmission electron microscopy (STEM) mass mapping has shown that microfibrils have a mass of ~2500 kDa per repeat [28] which is consistent with 8 fibrillin molecules in cross section which is supported by 3D reconstructions [29] and 2D images of microfibrils viewed in cross section [30,31]. After linear and lateral assembly, microfibrils are then further stabilised by the formation of transglutaminase cross links between their N- and C-termini [32].
Fibrillin microfibrils are flexible and have a hollow cylindrical appearance when visualised in three dimensions by electron microscopy with single particle image analysis, this is consistent with tube-like structures observed using quick freeze deep etch electron microscopy [29,33]. The microfibril can be described by three distinct regions based on their banding pattern, these have been termed the bead, arms and interbead regions [34,35] (Fig. 2). The microfibril bead region has a dense interwoven core surrounded by a ring structure which forms four arms which combine into the denser interbead region [29]. The bead region contains the N- and C-termini of the fibrillin molecules [24,153]. The microfibril is pseudo-symmetrical, supporting models that describe eight fibrillin molecules in cross-section [29,31]. Extracted microfibrils have a 56 nm repeating periodicity [34], similar to the 50–60 nm periodicity measured in tissues and can reversibly extend to ~80 nm [36,37]. Microfibril diameter is typically ~20 nm and does not vary from tissue to tissue [35] suggesting that this is carefully controlled during assembly, either limited by the packing of fibrillin molecules or by microfibril associated binding proteins.
How fibrillin molecules are organised into mature microfibrils however is still unclear. Extracted and recombinant fibrillin molecules have a length of ~148 nm [5,25] which does not reconcile readily with the periodicity of 56 nm seen for mature microfibrils. Therefore, several models of molecular organisation have been proposed which fall into two categories: the molecular folding model where a single molecule spans one 56 nm repeat [38,154] and staggered models where the fibrillin molecules are staggered by a half or a third and span two or three repeats [11,39]. Both packing models can explain antibody localisation of fibrillin regions within the microfibril, therefore higher resolution imaging or further labelling is required to provide resolution of the microfibril structure.
Microfibril assembly
Role of Heparan Sulphate in microfibril assembly
Although the precise mechanism of microfibril assembly is not fully understood, there is considerable evidence supporting the molecular and cellular interactions involved. Microfibril assembly consists of multimerization of the fibrillin molecules, deposition into the ECM, then recruitment of other microfibrillar components such as elastin and MAGP-1. It has been demonstrated that fibrillin monomers can multimerize by interactions between the N- and C-termini, as well as N—N and C—C interactions [25,26,40,41], also the interaction strength is increased between multimers of N- and C-terminal fragments [27]. Fibrillin expression and secretion alone is not sufficient to support microfibril formation, as demonstrated with fibrillin expressing HEK293 cells which have to be co-cultured with fibroblasts for matrix fibrillin microfibril deposition [42]. Other ECM molecules or specific cellular interactions are also required.
A key driver of microfibril assembly is interaction with Heparan Sulphate (HS). Heparan sulphate proteoglycans have a key role in the elastic fibre interactome [43], and HS has a strong interaction with fibrillin-1 at several sites [[44], [45], [46]]. HS has the ability to promote multimerization of fibrillin molecules prior to furin cleavage of newly secreted fibrillin [44,47] and fibrillin multimers also bind HS more strongly [48]. At higher concentrations, addition of heparin/HS is known to inhibit microfibril deposition [45,46,49]. HS is available through post-translational modifications on both membrane bound receptors, such as syndecans and glypicans, and non-membrane bound ECM molecules such as perlecan and agrin, where the interaction with perlecan and fibrillin-1 is via both HS and non-HS perlecan domains [50].
Requirement for fibronectin for microfibril assembly
Interactions with HS containing syndecans in conjunction with integrin binding of the RGD containing TB4 domain of fibrillin both influence fibrillin assembly. The fibrillin-1 RGD region primarily interacts with integrin α5β1 on fibroblasts but interactions with integrin αvβ3 were seen on other cell types [12], and it has been found that only fibrillin-1 fragments containing the RGD sequence support cell adhesion, for a variety different cell types including mesenchymal stem cells, chondrocyte progenitors and induced pluripotent stem cells [51,52]. However, unlike fibronectin, fibrillin does not need integrin mediated cell adhesion to assemble if fibronectin is also present [42]. Fibrillin microfibrils precede the evolution of the RGD site by 500 million years [53], indicating that the RGD site is not needed for microfibril assembly in invertebrates. The RGD site, integrins and fibronectin are only seen in vertebrate biology, and mutations affecting the TB4 domain of fibrillin result in altered microfibril deposition causing stiff skin syndrome [54], which can be recapitulated in mice by mutating the RGD site to RGE [55], suggesting for vertebrate microfibril deposition other more complex factors are needed via integrin mediated cell signalling. Indeed, it has also been found that interactions with the RGD site of fibrillin-1 by fibroblasts, control the expression of over one hundred microRNAs, some of which regulate TGFβ signalling (including miR-503) and focal adhesion formation (including miR-612 and miR-3185) [56]. Ancestral Fibrillin also preceded elastin which first appeared in gnathostomes (jawed vertebrates), so fibrillin did not evolve to assemble elastin. However the evolution of elastin which also led to the appearance of closed circulatory systems [57,58], also coincided with the divergence of ancestral fibrillin to fibrillin-1 and fibrillin 2/3 [53], although this period of duplication also known as 2R resulted in a large number of genetic changes.
In mesenchymal cells such as fibroblasts, fibrillin is deposited on the fibronectin network, and knockdown of fibronectin results in perturbation of fibrillin deposition in 2D cell cultures [59,60]. However In 3D mesenchymal cell cultures, fibronectin is located almost entirely in the outer cell layers, whilst fibrillin both colocalises with fibronectin on the outer cell layers but is also abundantly deposited in the tightly cell packed inner volume [61]. This suggests that fibrillin deposition can switch between fibronectin directed or cell surface interaction directed depending on the extracellular environment (Fig. 3).
Close cellular contact is also seen in epithelial cells sheets, where fibronectin is not required but does enhance deposition. In retinal pigmented epithelial cells, syndecan 4 as well as integrins α5β1 or α8β1 are required for microfibril deposition, and fibronectin is not needed but does enhance deposition [62]. The same study showed inhibition of cadherin junctions also disrupted microfibril deposition in retinal pigmented epithelial cells, and was independent of fibronectin deposition, indicating that the close cell-cell contact is needed for this mode of fibrillin deposition. It has been proposed that HS-rich cell junctions promote microfibril assembly, where fibronectin is not available [63].
Role of ADAMTS and ADAMTSL proteins in microfibril assembly
Members of the A Disintegrin And Metalloprotease with Thrombospondin type-1 repeats (ADAMTS) and ADAMTS-Like (ADAMTSL) family have been implicated in fibrillin microfibril assembly which influences elastic fibre formation. ADAMTS10 co-localises with microfibrils and enhances their deposition in vitro [64]. It is required for focal adhesion formation via interactions with both heparan sulphate and fibronectin [65]. Contrary to this, ADAMTS6 depletes HS reducing the number of focal adhesion complexes, required for fibrillin-1 microfibril deposition [65]. Therefore, the modulatory effects of both ADAMTS6 and -10 on focal adhesions play a vital role in microfibril deposition and subsequent elastic fibre assembly. Mouse models with disruption to ADAMTS10 show an accumulation of fibrillin-2 microfibrils in various tissues suggesting fibrillin-2 could be a substrate of ADAMTS10 [66,67]. ADAMTS17 co-localises with fibrillin-1, -2 and fibronectin fibres, binds to the N- and C-termini of fibrillin-2 but does not cleave either fibrillin-1 or -2 [68].
ADAMTS-Like proteins do not have catalytic activity but their interactions and localisation with fibrillin microfibrils support a regulatory role in microfibril formation and deposition. ADAMTSL2 binds to fibrillin-1 and the N-terminal binding site encompasses a fibrillin-1 mutation which results in Weill Marchesani Syndrome (WMS) [69]. ADAMTSL2 also binds to fibrillin-2 and deletion of ADAMTSL2 results in an accumulation of fibrillin-2 microfibrils [70]. ADAMTSL4 forms an independent fibrillar network which co-localises with fibrillin-1 microfibrils and enhances microfibril biogenesis [71,72]. Although interaction studies have demonstrated binding of ADAMTSL5 to fibrillin-1 and fibrillin-2, as well as its co-localisation with microfibrils, there is no evidence of ADAMTSL5 having a direct role in microfibril assembly [73]. On the other hand, ADAMTSL6α and -β variants promote fibrillin-1 microfibril biogenesis and localise with fibrillin-1 microfibrils in elastic and non-elastic tissues [74].
Tissue assembly of fibrillin microfibrils
In tissues, fibrillin microfibrils are organised into larger tissue specific structures which are important for the mechanical properties of that tissue. In the reticular dermis of skin, fibrillin-1 is formed into thick horizontally arranged elastic fibres which are connected to the dermal-epidermal junction through perpendicularly arranged bundles of microfibrils called elaunin and oxytalan fibres [75]. In normal skin, fibrillin-2 is only detected at the dermal-epidermal-junction and in vessel walls but has increased expression in wound healing [76]. In the lung, elastic fibres form branched networks which surround the alveoli allowing for elastic recoil during breathing and in the medial layer of the aorta, elastic fibres form sheets which surround layers of smooth muscle cells. In the ciliary zonule of the eye, microfibrils are found in the absence of elastin, here they bundle together to form ciliary zonule fibres. These fibres then form larger bundles which span between the ciliary body and the lens and deform the lens during accommodation. The large bundles of ciliary zonule fibres are held together by perpendicularly arranged ciliary zonule fibres which wrap around their circumference [29,77]. Microfibrils in the ciliary zonule are connected via bridging complexes [29,33], two candidates proteins for this role are ADAMTSL4 [78] and LTBP2 [79] which when absent result in ciliary zonule disruption.
Role of fibrillin in elastogenesis
Developmental expression of fibrillin and tropoelastin
In elastic tissues, elastic fibre assembly commences during early gestation with the expression and deposition of fibrillin microfibrils. In humans, fibrillin-1, -2 and -3 are expressed during development [80]; however, fibrillin-1 expression is the most abundant and dominates from late morphogenesis to adult life [81]. Moreover, proteomic data show that fibrillin isoform expression is both species and tissue dependent [82,83]. Fibrillin-3 is predominantly expressed in developing tissues, but the fibrillin-3 gene is disrupted in mice, so may be less important in mammals [8]. In developing elastic and non-elastic tissues, fibrillin-1 and -2 co-express and co-assemble in the matrix [84] and the requirement for both fibrillin-1 and fibrillin-2 isoforms has been demonstrated by a double knockout mouse model with early embryonic lethality [85]. Fibrillin microfibril deposition in developing elastic tissues precedes the expression of the elastin precursor, tropoelastin. Tropoelastin is highly expressed during embryogenesis, in comparison to the low levels detected in adult tissues [[86], [87], [88]].
The role of fibrillin in elastic fibre assembly
The assembly of elastic fibres in the ECM is a highly organised and multifaceted process requiring the expression and contribution of several ECM proteins.
The amorphous core of insoluble elastic fibres is comprised of cross-linked tropoelastin, glycosaminoglycans such as HS [89] and proteoglycans such a biglycan [90] deposited on a scaffold of co-assembled fibrillin-1 and -2 microfibrils [3]. Tropoelastin secretion is aided by elastin binding protein, an inactive splice variant of β-galactosidase [91], where C-terminal interactions with cell surface heparan and chondroitin sulphates mediate the coacervation of tropoelastin into larger dense globules [92,93]. Interactions between the hydrophobic regions of individual monomers results in the alignment of lysine residues that are enzymatically cross-linked by lysyl oxidase (LOX) and LOX-like 1 (LOXL1) to form larger aggregates [[94], [95], [96]]. Recently, we have shown that LOXL2 interacts with tropoelastin and LOXL2 catalyses the deamination of tropoelastin resulting in cross-linked tropoelastin peptides. The elastin-like material generated by LOXL2 was resistant to trypsin proteolysis and displayed mechanical properties similar to mature elastin. As LOXL2 co-distributes with elastin in the vascular wall this suggests that LOXL2 could participate in elastogenesis in vivo [97].
Once cross-linked, tropoelastin aggregates interact with co-assembled fibrillin-1 and -2 microfibrils near the cell surface via defined interactive domains. Tropoelastin interacts with microfibril associated glycoprotein-1 (MAGP1) [98,99] and MAGP1 interacts with the N-terminal region of fibrillin-1, suggesting tethering of tropoelastin to microfibrils [98,100]. A similar role for microfibrillar-associated protein 4 (MFAP4) is likely as it also binds to fibrillin and tropoelastin and promotes tropoelastin assembly [101]. Tropoelastin also directly interacts with the N-terminal region of fibrillin-1 via the TB2 domain and a covalent cross-link between tropoelastin and fibrillin is formed by transglutaminase-2 (TG2) [100,102]. The cross-link between the fibrillin TB2 domain and tropoelastin was mapped to residues Q669 in fibrillin and K38 in domain 4 of tropoelastin and addition of this region of fibrillin enhanced the coacervation of tropoelastin [103]. There is also a second high affinity binding site in the central region of fibrillin-1 encompassing the TB3 domain [102]. The initial deposition of tropoelastin aggregates onto fibrillin microfibrils is believed to be the primary step required for further coacervation and an augmentation of tropoelastin globule recruitment to form larger elastic fibres [103]. Once deposited on to fibrillin microfibrils, the tropoelastin aggregates coalesce to form stable, insoluble elastic fibres.
Microfibril binding proteins that facilitate elastogenesis
LTBPs in elastic fibre assembly
The LTBPs are extracellular glycoproteins in the fibrillin superfamily with similar modular domain structure [[104], [105], [106], [107]]. There are four LTBPs with LTBP1, -3 and -4 having important roles in the processing and secretion of TGFβ [108]. LTBP2 does not interact with TGFβ [109], but has a role in stabilising fibrillin microfibril bundles in the eye [79]. Indeed, dual functionalities have been proposed for members of the LTBP family, in either secretion of TGFβ or microfibril assembly and elastogenesis [110] (Fig. 4). LTBP1 has both long and short isoforms generated by alternate splicing at the N-terminus [111,112], as does LTBP4 [107,113]. Both LTBP2 and -4 have been implicated in the formation of elastic fibres in elastogenesis and LTBP2 and -4 have some commonalities in their functional roles, as LTBP4 can compensate for LTBP2 in some tissues [114]. However, even though LTBP3 and -4 are both expressed in the lung, they can only partially compensate for each other in lung development suggesting that the LTBP family have only some over-lapping functions [115].
Fibrillin is required for the deposition of LTBP2, -3 and -4 [116] but LTBP1 can be assembled in the absence of fibrillin [116]. In contrast, LTBP1 requires fibronectin for its deposition [116,117] and interacts with fibronectin [118]. Binding of LTBP1 to fibulin-4 may act as an additional mediator for fibrillin microfibril association [49,119]. The C-terminal region of LTBP1, -2 and -4 binds to fibrillin [120,121] but an equivalent region of LTBP3 does not interact with fibrillin [120] despite fibrillin being required for its deposition. LTBP1, -2 and -4 bind HS [[122], [123], [124]], suggesting they may interaction with HS proteoglycans (HSPGs) such as syndecans.
LTBP1 is a substrate for transglutaminase type II (TG2) and can be cross-linked into the matrix to enhance latency of the latent TGFβ complex [125,126]. Our recent study showed that both the N- and C-terminus of LTBP1 are substrates for TG2 and intermolecular N—N and N—C cross-links can form [122]. Oligomerisation of LTBP1 can occur in the absence of other proteins and is calcium dependent. LTBP1 multimerization is promoted by HS and stabilised by TG2 crosslinking suggesting a mechanism whereby LTBP1 filaments could support the bridging of fibrillin microfibrils to the matrix.
LTBP2 colocalises with elastic fibres and the deposition of LTBP2 into the matrix is dependent on the presence of a preformed fibrillin-1 network as fibrillin-1 knockdown disrupts LTBP2 deposition [127,128]. LTBP2 has been suggested to regulate elastic fibre formation in a fibrillin-independent manner via fibulin-5, and can compete for the fibulin-5 tropoelastin interaction potentially displacing elastin assemblies in elastogenesis [129,130]. LTBP3 is expressed in heart, skeletal muscle, prostate and ovaries [131] with interactions with fibrillin-1 important for matrix incorporation [116], although colocalisation of LTBP3 has been shown with fibronectin [118]. Secretion of LTBP3 requires co-expression with TGFβ and is dependent on binding to LAP [131,132].
Several studies have investigated the elastogenic role of LTBP4 where a dual functionality for LTBP4 has been proposed as a regulator of either elastic fibre assembly or TGFβ levels in lung [110,133]. LTBP4 is important in elastic fibre assembly with LTBP4 mutations resulting in Urban-Rifkin-Davis Syndrome (URDS) also known as autosomal recessive cutis laxa type 1C [134] which is replicated in knockout mouse models [135,136]. A lack of LTBP4 results in abnormal distribution and formation of elastic fibres [134,136]. Fibroblasts from URDS patients show increased TGFβ activity [134], consistent with data from LTBP4−/− mice [135,137]. However, reducing the level of TGFβ does not normalize elastogenesis indicating that LTBP4 has a dual functionality in regulating both elastogenesis and TGFβ signalling and the role of LTBP4 in elastogenesis is TGFβ independent [110].
Fibulin-4 and fibulin-5 in elastogenesis
Several elastic-fibre associated proteins are involved in the different stages of elastogenesis, from the micro-assembly of tropoelastin coacervates to the macro-assembly of elastic fibres. The fibulins are a multifunctional family of ECM glycoproteins comprising both long (fibulin-1, -2, -6) and short fibulins (fibulin-3, -4, -5, -7) [138]. Fibulin-1, -2, -3, -4, and -5 bind tropoelastin [139] and fibulin-2, -3, -4, and -5 are involved in elastic fibre formation. In particular, fibulin-4 and fibulin-5 (also known as developing arteries and neural crest EGF-like (DANCE)) play an important role in elastogenesis. Fibulin-4 and fibulin-5 null mice lack well-developed elastic fibres, demonstrating the importance of both glycoproteins in elastic fibre formation [[140], [141], [142]]. Functional studies have shown that fibulin-4 binds LOX with high affinity, which further results in a stronger interaction with tropoelastin, suggesting a role for fibulin-4 in the recruitment of LOX and the coacervation of tropoelastin [143,144]. Fibulin-5 has a strong interaction with tropoelastin and interacts with LOX, LOXL1, LOXL2 and LOXL4 to induce elastic fibre assembly and cross-linking [96,143,145]. Additionally, both fibulin-4 and -5 bind to the N-terminal region of fibrillin-1, suggesting a role in chaperoning tropoelastin aggregates to fibrillin microfibrils and facilitating the formation of cross-linked elastic fibres [139,143].
LTBP4 colocalises to and interacts with fibulin-5 via the four-cysteine domain at its N-terminus which binds to the C-terminal region of fibulin-5 [133]. LTBP4-fibulin interactions are important for elastogenesis as LTBP4 knockdown disrupts fibulin-5 and tropoelastin deposition which can be rescued by addition of LTBP4 [133]. These findings indicate that LTBP4 is essential for proper deposition of fibulin-5-elastin complexes onto fibrillin microfibril scaffolds. LTBP4 also interacts with fibulin-4 and fibulin-4 deposition is disrupted in LTBP4−/− mice but normal in LTBP4S−/− mice that express the LTBP4L isoform [136,146]. This raised the question whether the different LTBP4 isoforms differentially bind fibulin-4. Indeed mice expressing only the LTBP4L isoform with reduced expression of fibulin-4 die during the early postnatal period [146]. In contrast LTBP4S−/−;fibulin-4R/R mice survive to adulthood [135,147], indicating that LTBP4L interacts with fibulin-4 and this interaction is essential for survival [146]. Together these findings imply that the elastogenic role of LTBP4 is both fibulin-4 and fibulin-5 dependent and that fibulin-5 cannot compensate for fibulin-4. Moreover, LTBP4S favours binding to fibulin-5 [133], whereas LTBP4L favours binding to fibulin-4 [136]. Overall, both LTBP4 isoforms are required for deposition of both fibulin-5-elastin and fibulin-4-elastin complexes onto fibrillin microfibrils.
The Emilins in elastic fibre formation
Emilin (Elastin Microfibril Interface-Located ProteIN)-1 and -2 are found at sites where elastin and fibrillin microfibrils are in close proximity [148]. The Emilins are deposited on and co-regulated with fibrillin-1 [149] and they are required for elastic fibre formation. They have a regulatory role in cell adhesion, migration and wound healing, and have been implicated in blood vascular morphology, tumour cell invasiveness and dermal proliferation [[149], [150], [151]]. Fibulin-4 has been identified as an Emilin-1 binding partner with Emilin-1 knockdown preventing fibulin-4 deposition, suggesting a requirement for Emilin-1 in fibulin-4 incorporation in the matrix [152].
Final considerations
Fibrillin is large, modular, extracellular matrix glycoprotein that assembles into beaded microfibrils which have roles in elastic fibre assembly, elastic tissue function and extracellular signalling events. In most tissues, fibrillin microfibrils associate with elastin to form elastic fibres and hence make key contributions to the elastic function of these tissues acting as a stiff reinforcer of elastin-containing tissues. Fibrillin microfibrils also provide limited elasticity in tissues devoid of elastin. They also provide a multifunctional platform for the interaction of many matrix molecules required for elastic fibre assembly and function and provide a connection to the cell surface. Fibrillin is needed for the correct assembly of many microfibril associated proteins, including members of the LTBP family, and mediate interactions between fibulin-4 or fibulin-5 and LTBPs or LOX/L enzymes facilitating their functions. Indeed fibrillin microfibril and elastic fibre biology is highly complex which provides a challenge to the research community to unravel the multiple molecular and cellular interactions that underpin elastogenesis. However, understanding these events provides a future opportunity to inform future regenerative medicine strategies and intervene in disease processes.
Acknowledgements
The Wellcome Trust Centre for Cell-Matrix Research is supported by funding from the Wellcome Trust (088785/Z/09/Z). C·B gratefully acknowledges BBSRC funding (Ref: BB/N015398/1, BB/R008221/1 and BB/S015779/1).
Contributor Information
Stuart A. Cain, Email: stuart.a.cain@manchester.ac.uk.
Clair Baldock, Email: clair.baldock@manchester.ac.uk.
References
- 1.Thomson J., Singh M., Eckersley A., Cain S.A., Sherratt M.J., Baldock C. Fibrillin microfibrils and elastic fibre proteins: functional interactions and extracellular regulation of growth factors. Semin. Cell Dev. Biol. 2019;89:109–117. doi: 10.1016/j.semcdb.2018.07.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Mecham R.P. Elastin in lung development and disease pathogenesis. Matrix Biol. 2018;73:6–20. doi: 10.1016/j.matbio.2018.01.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Wagenseil J.E., Mecham R.P. New insights into elastic fiber assembly. Birth Defects Res C Embryo Today. 2007;81(4):229–240. doi: 10.1002/bdrc.20111. [DOI] [PubMed] [Google Scholar]
- 4.Sengle G., Sakai L.Y. The fibrillin microfibril scaffold: a niche for growth factors and mechanosensation? Matrix Biol. 2015;47:3–12. doi: 10.1016/j.matbio.2015.05.002. [DOI] [PubMed] [Google Scholar]
- 5.Sakai L.Y., Keene D.R., Glanville R.W., Bachinger H.P. Purification and partial characterization of fibrillin, a cysteine-rich structural component of connective tissue microfibrils. J. Biol. Chem. 1991;266(22):14763–14770. [PubMed] [Google Scholar]
- 6.Pereira L., D'Alessio M., Ramirez F., Lynch J.R., Sykes B., Pangilinan T., Bonadio J. Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan syndrome. Hum. Mol. Genet. 1993;2(7):961–968. doi: 10.1093/hmg/2.7.961. [DOI] [PubMed] [Google Scholar]
- 7.Zhang H., Apfelroth S.D., Hu W., Davis E.C., Sanguineti C., Bonadio J., Mecham R.P., Ramirez F. Structure and expression of fibrillin-2, a novel microfibrillar component preferentially located in elastic matrices. J. Cell Biol. 1994;124(5):855–863. doi: 10.1083/jcb.124.5.855. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Corson G.M., Charbonneau N.L., Keene D.R., Sakai L.Y. Differential expression of fibrillin-3 adds to microfibril variety in human and avian, but not rodent, connective tissues. Genomics. 2004;83(3):461–472. doi: 10.1016/j.ygeno.2003.08.023. [DOI] [PubMed] [Google Scholar]
- 9.Maslen C.L., Corson G.M., Maddox B.K., Glanville R.W., Sakai L.Y. Partial sequence of a candidate gene for the Marfan syndrome. Nature. 1991;352(6333):334–337. doi: 10.1038/352334a0. [DOI] [PubMed] [Google Scholar]
- 10.Yuan X., Downing A.K., Knott V., Handford P.A. Solution structure of the transforming growth factor beta-binding protein-like module, a domain associated with matrix fibrils. EMBO J. 1997;16(22):6659–6666. doi: 10.1093/emboj/16.22.6659. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Lee S.S., Knott V., Jovanovic J., Harlos K., Grimes J.M., Choulier L., Mardon H.J., Stuart D.I., Handford P.A. Structure of the integrin binding fragment from fibrillin-1 gives new insights into microfibril organization. Structure (London, England: 1993) 2004;12(4):717–729. doi: 10.1016/j.str.2004.02.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Bax D.V., Bernard S.E., Lomas A., Morgan A., Humphries J., Shuttleworth C.A., Humphries M.J., Kielty C.M. Cell adhesion to fibrillin-1 molecules and microfibrils is mediated by alpha 5 beta 1 and alpha v beta 3 integrins. J. Biol. Chem. 2003;278(36):34605–34616. doi: 10.1074/jbc.M303159200. [DOI] [PubMed] [Google Scholar]
- 13.Jovanovic J., Takagi J., Choulier L., Abrescia N.G., Stuart D.I., van der Merwe P.A., Mardon H.J., Handford P.A. AlphaVbeta6 is a novel receptor for human fibrillin-1. Comparative studies of molecular determinants underlying integrin-rgd affinity and specificity. J. Biol. Chem. 2007;282(9):6743–6751. doi: 10.1074/jbc.M607008200. [DOI] [PubMed] [Google Scholar]
- 14.Sakamoto H., Broekelmann T., Cheresh D.A., Ramirez F., Rosenbloom J., Mecham R.P. Cell-type specific recognition of RGD- and non-RGD-containing cell binding domains in fibrillin-1. J. Biol. Chem. 1996;271(9):4916–4922. [PubMed] [Google Scholar]
- 15.Pfaff M., Reinhardt D.P., Sakai L.Y., Timpl R. Cell adhesion and integrin binding to recombinant human fibrillin-1. FEBS Lett. 1996;384(3):247–250. doi: 10.1016/0014-5793(96)00325-0. [DOI] [PubMed] [Google Scholar]
- 16.Jensen S.A., Iqbal S., Lowe E.D., Redfield C., Handford P.A. Structure and interdomain interactions of a hybrid domain: a disulphide-rich module of the fibrillin/LTBP superfamily of matrix proteins. Structure (London, England: 1993) 2009;17(5):759–768. doi: 10.1016/j.str.2009.03.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Corson G.M., Chalberg S.C., Dietz H.C., Charbonneau N.L., Sakai L.Y. Fibrillin binds calcium and is coded by cDNAs that reveal a multidomain structure and alternatively spliced exons at the 5′ end. Genomics. 1993;17(2):476–484. doi: 10.1006/geno.1993.1350. [DOI] [PubMed] [Google Scholar]
- 18.Wallis D.D., Putnam E.A., Cretoiu J.S., Carmical S.G., Cao S.N., Thomas G., Milewicz D.M. Profibrillin-1 maturation by human dermal fibroblasts: proteolytic processing and molecular chaperones. J. Cell. Biochem. 2003;90(3):641–652. doi: 10.1002/jcb.10657. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Jensen S.A., Aspinall G., Handford P.A. C-terminal propeptide is required for fibrillin-1 secretion and blocks premature assembly through linkage to domains cbEGF41-43. Proc. Natl. Acad. Sci. U. S. A. 2014;111(28):10155–10160. doi: 10.1073/pnas.1401697111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Lonnqvist L., Reinhardt D., Sakai L., Peltonen L. Evidence for furin-type activity-mediated C-terminal processing of profibrillin-1 and interference in the processing by certain mutations. Hum. Mol. Genet. 1998;7(13):2039–2044. doi: 10.1093/hmg/7.13.2039. [DOI] [PubMed] [Google Scholar]
- 21.Romere C., Duerrschmid C., Bournat J., Constable P., Jain M., Xia F., Saha P.K., Del Solar M., Zhu B., York B., Sarkar P., Rendon D.A., Gaber M.W., LeMaire S.A., Coselli J.S., Milewicz D.M., Sutton V.R., Butte N.F., Moore D.D., Chopra A.R. Asprosin, a fasting-induced glucogenic protein hormone. Cell. 2016;165(3):566–579. doi: 10.1016/j.cell.2016.02.063. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Tagliabracci V.S., Wiley S.E., Guo X., Kinch L.N., Durrant E., Wen J., Xiao J., Cui J., Nguyen K.B., Engel J.L., Coon J.J., Grishin N., Pinna L.A., Pagliarini D.J., Dixon J.E. A single kinase generates the majority of the secreted phosphoproteome. Cell. 2015;161(7):1619–1632. doi: 10.1016/j.cell.2015.05.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Keene D.R., Maddox B.K., Kuo H.J., Sakai L.Y., Glanville R.W. Extraction of extendable beaded structures and their identification as fibrillin-containing extracellular matrix microfibrils. J. Histochem. Cytochem. 1991;39(4):441–449. doi: 10.1177/39.4.2005373. [DOI] [PubMed] [Google Scholar]
- 24.Reinhardt D.P., Keene D.R., Corson G.M., Poschl E., Bachinger H.P., Gambee J.E., Sakai L.Y. Fibrillin-1: organization in microfibrils and structural properties. J. Mol. Biol. 1996;258(1):104–116. doi: 10.1006/jmbi.1996.0237. [DOI] [PubMed] [Google Scholar]
- 25.Lin G., Tiedemann K., Vollbrandt T., Peters H., Batge B., Brinckmann J., Reinhardt D.P. Homo- and heterotypic fibrillin-1 and -2 interactions constitute the basis for the assembly of microfibrils. J. Biol. Chem. 2002;277(52):50795–50804. doi: 10.1074/jbc.M210611200. [DOI] [PubMed] [Google Scholar]
- 26.Marson A., Rock M.J., Cain S.A., Freeman L.J., Morgan A., Mellody K., Shuttleworth C.A., Baldock C., Kielty C.M. Homotypic fibrillin-1 interactions in microfibril assembly. J. Biol. Chem. 2005;280(6):5013–5021. doi: 10.1074/jbc.M409029200. [DOI] [PubMed] [Google Scholar]
- 27.Hubmacher D., El-Hallous E.I., Nelea V., Kaartinen M.T., Lee E.R., Reinhardt D.P. Biogenesis of extracellular microfibrils: multimerization of the fibrillin-1 C terminus into bead-like structures enables self-assembly. Proc. Natl. Acad. Sci. U. S. A. 2008;105(18):6548–6553. doi: 10.1073/pnas.0706335105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Sherratt M.J., Holmes D.F., Shuttleworth C.A., Kielty C.M. Scanning transmission electron microscopy mass analysis of fibrillin-containing microfibrils from foetal elastic tissues. Int. J. Biochem. Cell Biol. 1997;29(8–9):1063–1070. doi: 10.1016/s1357-2725(97)00028-9. [DOI] [PubMed] [Google Scholar]
- 29.Godwin A.R.F., Starborg T., Smith D.J., Sherratt M.J., Roseman A.M., Baldock C. Multiscale imaging reveals the hierarchical organization of fibrillin microfibrils. J. Mol. Biol. 2018;430(21):4142–4155. doi: 10.1016/j.jmb.2018.08.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Cleary E.G., Gibson M.A. Elastin-associated microfibrils and microfibrillar proteins. International review of connective tissue research. 1983;10:97–209. doi: 10.1016/b978-0-12-363710-9.50009-5. [DOI] [PubMed] [Google Scholar]
- 31.Wang M.C., Lu Y., Baldock C. Fibrillin microfibrils: a key role for the interbead region in elasticity. J. Mol. Biol. 2009;388(1):168–179. doi: 10.1016/j.jmb.2009.02.062. [DOI] [PubMed] [Google Scholar]
- 32.Qian R.Q., Glanville R.W. Alignment of fibrillin molecules in elastic microfibrils is defined by transglutaminase-derived cross-links. Biochemistry. 1997;36(50):15841–15847. doi: 10.1021/bi971036f. [DOI] [PubMed] [Google Scholar]
- 33.Davis E.C., Roth R.A., Heuser J.E., Mecham R.P. Ultrastructural properties of ciliary zonule microfibrils. J. Struct. Biol. 2002;139(2):65–75. doi: 10.1016/s1047-8477(02)00559-2. [DOI] [PubMed] [Google Scholar]
- 34.Sherratt M.J., Wess T.J., Baldock C., Ashworth J., Purslow P.P., Shuttleworth C.A., Kielty C.M. Fibrillin-rich microfibrils of the extracellular matrix: ultrastructure and assembly. Micron (Oxford, England: 1993) 2001;32(2):185–200. doi: 10.1016/s0968-4328(99)00082-7. [DOI] [PubMed] [Google Scholar]
- 35.Lu Y., Sherratt M.J., Wang M.C., Baldock C. Tissue specific differences in fibrillin microfibrils analysed using single particle image analysis. J. Struct. Biol. 2006;155(2):285–293. doi: 10.1016/j.jsb.2006.03.021. [DOI] [PubMed] [Google Scholar]
- 36.Sherratt M.J., Baldock C., Haston J.L., Holmes D.F., Jones C.J., Shuttleworth C.A., Wess T.J., Kielty C.M. Fibrillin microfibrils are stiff reinforcing fibres in compliant tissues. J. Mol. Biol. 2003;332(1):183–193. doi: 10.1016/s0022-2836(03)00829-5. [DOI] [PubMed] [Google Scholar]
- 37.Wess T.J., Purslow P.P., Kielty C.M. X-ray diffraction studies of fibrillin-rich microfibrils: effects of tissue extension on axial and lateral packing. J. Struct. Biol. 1998;122(1–2):123–127. doi: 10.1006/jsbi.1998.3992. [DOI] [PubMed] [Google Scholar]
- 38.Baldock C., Siegler V., Bax D.V., Cain S.A., Mellody K.T., Marson A., Haston J.L., Berry R., Wang M.C., Grossmann J.G., Roessle M., Kielty C.M., Wess T.J. Nanostructure of fibrillin-1 reveals compact conformation of EGF arrays and mechanism for extensibility. Proc. Natl. Acad. Sci. U. S. A. 2006;103(32):11922–11927. doi: 10.1073/pnas.0601609103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Kuo C.L., Isogai Z., Keene D.R., Hazeki N., Ono R.N., Sengle G., Bachinger H.P., Sakai L.Y. Effects of fibrillin-1 degradation on microfibril ultrastructure. J. Biol. Chem. 2007;282(6):4007–4020. doi: 10.1074/jbc.M606370200. [DOI] [PubMed] [Google Scholar]
- 40.Ashworth J.L., Kelly V., Rock M.J., Shuttleworth C.A., Kielty C.M. Regulation of fibrillin carboxy-terminal furin processing by N-glycosylation, and association of amino- and carboxy-terminal sequences. J. Cell Sci. 1999;112(Pt 22):4163–4171. doi: 10.1242/jcs.112.22.4163. [DOI] [PubMed] [Google Scholar]
- 41.Trask T.M., Ritty T.M., Broekelmann T., Tisdale C., Mecham R.P. N-terminal domains of fibrillin 1 and fibrillin 2 direct the formation of homodimers: a possible first step in microfibril assembly. Biochem. J. 1999;340(Pt 3):693–701. [PMC free article] [PubMed] [Google Scholar]
- 42.Hubmacher D., Bergeron E., Fagotto-Kaufmann C., Sakai L.Y., Reinhardt D.P. Early fibrillin-1 assembly monitored through a modifiable recombinant cell approach. Biomacromolecules. 2014;15(4):1456–1468. doi: 10.1021/bm5000696. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Cain S.A., McGovern A., Small E., Ward L.J., Baldock C., Shuttleworth A., Kielty C.M. Defining elastic fiber interactions by molecular fishing: an affinity purification and mass spectrometry approach. Mol. Cell. Proteomics. 2009;8(12):2715–2732. doi: 10.1074/mcp.M900008-MCP200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Cain S.A., Baldwin A.K., Mahalingam Y., Raynal B., Jowitt T.A., Shuttleworth C.A., Couchman J.R., Kielty C.M. Heparan sulfate regulates fibrillin-1 N- and C-terminal interactions. J. Biol. Chem. 2008;283(40):27017–27027. doi: 10.1074/jbc.M803373200. [DOI] [PubMed] [Google Scholar]
- 45.Ritty T.M., Broekelmann T.J., Werneck C.C., Mecham R.P. Fibrillin-1 and -2 contain heparin-binding sites important for matrix deposition and that support cell attachment. Biochem. J. 2003;375(Pt 2):425–432. doi: 10.1042/BJ20030649. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Tiedemann K., Batge B., Muller P.K., Reinhardt D.P. Interactions of fibrillin-1 with heparin/heparan sulfate, implications for microfibrillar assembly. J. Biol. Chem. 2001;276(38):36035–36042. doi: 10.1074/jbc.M104985200. [DOI] [PubMed] [Google Scholar]
- 47.Yadin D.A., Robertson I.B., McNaught-Davis J., Evans P., Stoddart D., Handford P.A., Jensen S.A., Redfield C. Structure of the fibrillin-1 N-terminal domains suggests that heparan sulfate regulates the early stages of microfibril assembly. Structure (London, England: 1993) 2013;21(10):1743–1756. doi: 10.1016/j.str.2013.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Sabatier L., Djokic J., Hubmacher D., Dzafik D., Nelea V., Reinhardt D.P. Heparin/heparan sulfate controls fibrillin-1, -2 and -3 self-interactions in microfibril assembly. FEBS Lett. 2014;588:2890–2897. doi: 10.1016/j.febslet.2014.06.061. [DOI] [PubMed] [Google Scholar]
- 49.Massam-Wu T., Chiu M., Choudhury R., Chaudhry S.S., Baldwin A.K., McGovern A., Baldock C., Shuttleworth C.A., Kielty C.M. Assembly of fibrillin microfibrils governs extracellular deposition of latent TGF{beta} J. Cell Sci. 2010;123(Pt 17):3006–3018. doi: 10.1242/jcs.073437. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Tiedemann K., Sasaki T., Gustafsson E., Gohring W., Batge B., Notbohm H., Timpl R., Wedel T., Schlotzer-Schrehardt U., Reinhardt D.P. Microfibrils at basement membrane zones interact with perlecan via fibrillin-1. J. Biol. Chem. 2005;280(12):11404–11412. doi: 10.1074/jbc.M409882200. [DOI] [PubMed] [Google Scholar]
- 51.Cheng A., Cain S.A., Tian P., Baldwin A.K., Uppanan P., Kielty C.M., Kimber S.J. Recombinant extracellular matrix protein fragments support human embryonic stem cell chondrogenesis. Tissue Eng Part A. 2018;24(11−12):968–978. doi: 10.1089/ten.tea.2017.0285. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52.Leha A., Moens N., Meleckyte R., Culley O.J., Gervasio M.K., Kerz M., Reimer A., Cain S.A., Streeter I., Folarin A., Stegle O., Kielty C.M., HipSci C., Durbin R., Watt F.M., Danovi D. A high-content platform to characterise human induced pluripotent stem cell lines. Methods. 2016;96:85–96. doi: 10.1016/j.ymeth.2015.11.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53.Piha-Gossack A., Sossin W., Reinhardt D.P. The evolution of extracellular fibrillins and their functional domains. PLoS One. 2012;7(3) doi: 10.1371/journal.pone.0033560. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 54.Loeys B.L., Gerber E.E., Riegert-Johnson D., Iqbal S., Whiteman P., McConnell V., Chillakuri C.R., Macaya D., Coucke P.J., De Paepe A., Judge D.P., Wigley F., Davis E.C., Mardon H.J., Handford P., Keene D.R., Sakai L.Y., Dietz H.C. Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci Transl Med. 2010;2(23) doi: 10.1126/scitranslmed.3000488. (23ra20) [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Gerber E.E., Gallo E.M., Fontana S.C., Davis E.C., Wigley F.M., Huso D.L., Dietz H.C. Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma. Nature. 2013;503(7474):126–130. doi: 10.1038/nature12614. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 56.Zeyer K.A., Zhang R.-M., Kumra H., Hassan A., Reinhardt D.P. The fibrillin-1 RGD integrin binding site regulates gene expression and cell function through microRNAs. J. Mol. Biol. 2019;431(2):401–421. doi: 10.1016/j.jmb.2018.11.021. [DOI] [PubMed] [Google Scholar]
- 57.Chung M.I.S., Ming M., Stahl R.J., Chan E., Parkinson J., Keeley F.W. Sequences and domain structures of mammalian, avian, amphibian and teleost tropoelastins: clues to the evolutionary history of elastins. Matrix Biol. 2006;25(8):492–504. doi: 10.1016/j.matbio.2006.08.258. [DOI] [PubMed] [Google Scholar]
- 58.Faury G. Function-structure relationship of elastic arteries in evolution: from microfibrils to elastin and elastic fibres. Pathol Biol (Paris) 2001;49(4):310–325. doi: 10.1016/s0369-8114(01)00147-x. [DOI] [PubMed] [Google Scholar]
- 59.Sabatier L., Chen D., Fagotto-Kaufmann C., Hubmacher D., McKee M.D., Annis D.S., Mosher D.F., Reinhardt D.P. Fibrillin assembly requires fibronectin. Mol. Biol. Cell. 2009;20(3):846–858. doi: 10.1091/mbc.E08-08-0830. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Kinsey R., Williamson M.R., Chaudhry S., Mellody K.T., McGovern A., Takahashi S., Shuttleworth C.A., Kielty C.M. Fibrillin-1 microfibril deposition is dependent on fibronectin assembly. J. Cell Sci. 2008;121(Pt 16):2696–2704. doi: 10.1242/jcs.029819. [DOI] [PubMed] [Google Scholar]
- 61.Redondo-Castro E., Cunningham C.J., Miller J., Cain S.A., Allan S.M., Pinteaux E. Generation of human mesenchymal stem cell 3D spheroids using low-binding plates. Bio Protoc. 2018;8(16) doi: 10.21769/BioProtoc.2968. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Baldwin A.K., Cain S.A., Lennon R., Godwin A., Merry C.L., Kielty C.M. Epithelial-mesenchymal status influences how cells deposit fibrillin microfibrils. J. Cell Sci. 2014;127(Pt 1):158–171. doi: 10.1242/jcs.134270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Kielty C.M. Fell-Muir Lecture: fibrillin microfibrils: structural tensometers of elastic tissues? Int. J. Exp. Pathol. 2017;98(4):172–190. doi: 10.1111/iep.12239. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Kutz W.E., Wang L.W., Bader H.L., Majors A.K., Iwata K., Traboulsi E.I., Sakai L.Y., Keene D.R., Apte S.S. ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts. J. Biol. Chem. 2011;286(19):17156–17167. doi: 10.1074/jbc.M111.231571. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Cain S.A., Mularczyk E.J., Singh M., Massam-Wu T., Kielty C.M. ADAMTS-10 and -6 differentially regulate cell-cell junctions and focal adhesions. Sci. Rep. 2016;6:35956. doi: 10.1038/srep35956. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66.Mularczyk E.J., Singh M., Godwin A.R.F., Galli F., Humphreys N., Adamson A.D., Mironov A., Cain S.A., Sengle G., Boot-Handford R.P., Cossu G., Kielty C.M., Baldock C. ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome. Hum. Mol. Genet. 2018;27(21):3675–3687. doi: 10.1093/hmg/ddy276. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67.Wang L.W., Kutz W.E., Mead T.J., Beene L.C., Singh S., Jenkins M.W., Reinhardt D.P., Apte S.S. Adamts10 inactivation in mice leads to persistence of ocular microfibrils subsequent to reduced fibrillin-2 cleavage. Matrix Biol. 2019;77:117–128. doi: 10.1016/j.matbio.2018.09.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68.Hubmacher D., Schneider M., Berardinelli S.J., Takeuchi H., Willard B., Reinhardt D.P., Haltiwanger R.S., Apte S.S. Unusual life cycle and impact on microfibril assembly of ADAMTS17, a secreted metalloprotease mutated in genetic eye disease. Sci. Rep. 2017;7:41871. doi: 10.1038/srep41871. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69.Sengle G., Tsutsui K., Keene D.R., Tufa S.F., Carlson E.J., Charbonneau N.L., Ono R.N., Sasaki T., Wirtz M.K., Samples J.R., Fessler L.I., Fessler J.H., Sekiguchi K., Hayflick S.J., Sakai L.Y. Microenvironmental regulation by fibrillin-1. PLoS Genet. 2012;8(1) doi: 10.1371/journal.pgen.1002425. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Hubmacher D., Wang L.W., Mecham R.P., Reinhardt D.P., Apte S.S. Adamtsl2 deletion results in bronchial fibrillin microfibril accumulation and bronchial epithelial dysplasia – a novel mouse model providing insights into geleophysic dysplasia. Dis. Model. Mech. 2015;8(5):487–499. doi: 10.1242/dmm.017046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71.Gabriel L.A., Wang L.W., Bader H., Ho J.C., Majors A.K., Hollyfield J.G., Traboulsi E.I., Apte S.S. ADAMTSL4, a secreted glycoprotein widely distributed in the eye, binds fibrillin-1 microfibrils and accelerates microfibril biogenesis. Invest. Ophthalmol. Vis. Sci. 2012;53(1):461–469. doi: 10.1167/iovs.10-5955. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72.Chandra A., Jones M., Cottrill P., Eastlake K., Limb G.A., Charteris D.G. Gene expression and protein distribution of ADAMTSL-4 in human iris, choroid and retina. Br. J. Ophthalmol. 2013;97(9):1208–1212. doi: 10.1136/bjophthalmol-2013-303353. [DOI] [PubMed] [Google Scholar]
- 73.Bader H.L., Wang L.W., Ho J.C., Tran T., Holden P., Fitzgerald J., Atit R.P., Reinhardt D.P., Apte S.S. A disintegrin-like and metalloprotease domain containing thrombospondin type 1 motif-like 5 (ADAMTSL5) is a novel fibrillin-1-, fibrillin-2-, and heparin-binding member of the ADAMTS superfamily containing a netrin-like module. Matrix Biol. 2012;31(7):398–411. doi: 10.1016/j.matbio.2012.09.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Tsutsui K., Manabe R., Yamada T., Nakano I., Oguri Y., Keene D.R., Sengle G., Sakai L.Y., Sekiguchi K. ADAMTSL-6 is a novel extracellular matrix protein that binds to fibrillin-1 and promotes fibrillin-1 fibril formation. J. Biol. Chem. 2010;285(7):4870–4882. doi: 10.1074/jbc.M109.076919. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Braverman I.M., Fonferko E. Studies in cutaneous aging: I. The elastic fiber network. J. Investig. Dermatol. 1982;78(5):434–443. doi: 10.1111/1523-1747.ep12507866. [DOI] [PubMed] [Google Scholar]
- 76.Brinckmann J., Hunzelmann N., Kahle B., Rohwedel J., Kramer J., Gibson M.A., Hubmacher D., Reinhardt D.P. Enhanced fibrillin-2 expression is a general feature of wound healing and sclerosis: potential alteration of cell attachment and storage of TGF-beta. Lab. Investig. 2010;90(5):739–752. doi: 10.1038/labinvest.2010.49. [DOI] [PubMed] [Google Scholar]
- 77.Hiraoka M., Inoue K., Ohtaka-Maruyama C., Ohsako S., Kojima N., Senoo H., Takada M. Intracapsular organization of ciliary zonules in monkey eyes. Anat. Rec. 2010;293(10):1797–1804. doi: 10.1002/ar.21220. [DOI] [PubMed] [Google Scholar]
- 78.Collin G.B., Hubmacher D., Charette J.R., Hicks W.L., Stone L., Yu M., Naggert J.K., Krebs M.P., Peachey N.S., Apte S.S., Nishina P.M. Disruption of murine Adamtsl4 results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation. Hum. Mol. Genet. 2015;24(24):6958–6974. doi: 10.1093/hmg/ddv399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79.Inoue T., Ohbayashi T., Fujikawa Y., Yoshida H., Akama T.O., Noda K., Horiguchi M., Kameyama K., Hata Y., Takahashi K., Kusumoto K., Nakamura T. Latent TGF-beta binding protein-2 is essential for the development of ciliary zonule microfibrils. Hum. Mol. Genet. 2014;23(21):5672–5682. doi: 10.1093/hmg/ddu283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80.Zhang H., Hu W., Ramirez F. Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils. J. Cell Biol. 1995;129:1165–1176. doi: 10.1083/jcb.129.4.1165. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81.Sabatier L., Miosge N., Hubmacher D., Lin G., Davis E.C., Reinhardt D.P. Fibrillin-3 expression in human development. Matrix Biol. 2011;30(1):43–52. doi: 10.1016/j.matbio.2010.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82.Cain S.A., Morgan A., Sherratt M.J., Ball S.G., Shuttleworth C.A., Kielty C.M. Proteomic analysis of fibrillin-rich microfibrils. Proteomics. 2006;6(1):111–122. doi: 10.1002/pmic.200401340. [DOI] [PubMed] [Google Scholar]
- 83.De Maria A., Wilmarth P.A., David L.L., Bassnett S. Proteomic analysis of the bovine and human ciliary zonule. Invest. Ophthalmol. Vis. Sci. 2017;58(1):573–585. doi: 10.1167/iovs.16-20866. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.Charbonneau N.L., Dzamba B.J., Ono R.N., Keene D.R., Corson G.M., Reinhardt D.P., Sakai L.Y. Fibrillins can co-assemble in fibrils, but fibrillin fibril composition displays cell-specific differences. J. Biol. Chem. 2003;278(4):2740–2749. doi: 10.1074/jbc.M209201200. [DOI] [PubMed] [Google Scholar]
- 85.Carta L., Pereira L., Arteaga-Solis E., Lee-Arteaga S.Y., Lenart B., Starcher B., Merkel C.A., Sukoyan M., Kerkis A., Hazeki N., Keene D.R., Sakai L.Y., Ramirez F. Fibrillins 1 and 2 perform partially overlapping functions during aortic development. J. Biol. Chem. 2006;281(12):8016–8023. doi: 10.1074/jbc.M511599200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86.Duque Lasio M.L., Kozel B.A. Elastin-driven genetic diseases. Matrix Biol. 2018;71-72:144–160. doi: 10.1016/j.matbio.2018.02.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 87.Fazio M.J., Mattei M.G., Passage E., Chu M.L., Black D., Solomon E., Davidson J.M., Uitto J. Human elastin gene: new evidence for localization to the long arm of chromosome 7. Am. J. Hum. Genet. 1991;48(4):696–703. [PMC free article] [PubMed] [Google Scholar]
- 88.Swee M.H., Parks W., Pierce R. Developmental regulation of elastin production: Expression of tropoelastin pre-mRNA persists after down-regulation of steady-state mRNA levels. J. Biol. Chem. 1995;270:14899–14906. doi: 10.1074/jbc.270.25.14899. [DOI] [PubMed] [Google Scholar]
- 89.Gheduzzi D., Guerra D., Bochicchio B., Pepe A., Tamburro A.M., Quaglino D., Mithieux S., Weiss A.S., Pasquali Ronchetti I. Heparan sulphate interacts with tropoelastin, with some tropoelastin peptides and is present in human dermis elastic fibers. Matrix Biol. 2005;24(1):15–25. doi: 10.1016/j.matbio.2004.12.001. [DOI] [PubMed] [Google Scholar]
- 90.Reinboth B., Hanssen E., Cleary E.G., Gibson M.A. Molecular interactions of biglycan and decorin with elastic fiber components: biglycan forms a ternary complex with tropoelastin and microfibril-associated glycoprotein 1. J. Biol. Chem. 2002;277(6):3950–3957. doi: 10.1074/jbc.M109540200. [DOI] [PubMed] [Google Scholar]
- 91.Hinek A., Rabinovitch M. 67-kD elastin-binding protein is a protective “companion” of extracellular insoluble elastin and intracellular tropoelastin. J. Cell Biol. 1994;126(2):563–574. doi: 10.1083/jcb.126.2.563. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 92.Broekelmann T.J., Kozel B.A., Ishibashi H., Werneck C.C., Keeley F.W., Zhang L., Mecham R.P. Tropoelastin interacts with cell-surface glycosaminoglycans via its COOH-terminal domain. J. Biol. Chem. 2005;280(49):40939–40947. doi: 10.1074/jbc.M507309200. [DOI] [PubMed] [Google Scholar]
- 93.Kozel B.A., Rongish B.J., Czirok A., Zach J., Little C.D., Davis E.C., Knutsen R.H., Wagenseil J.E., Levy M.A., Mecham R.P. Elastic fiber formation: a dynamic view of extracellular matrix assembly using timer reporters. J. Cell. Physiol. 2006;207(1):87–96. doi: 10.1002/jcp.20546. [DOI] [PubMed] [Google Scholar]
- 94.Dyksterhuis L.B., Baldock C., Lammie D., Wess T.J., Weiss A.S. Domains 17–27 of tropoelastin contain key regions of contact for coacervation and contain an unusual turn-containing crosslinking domain. Matrix Biol. 2007;26(2):125–135. doi: 10.1016/j.matbio.2006.10.002. [DOI] [PubMed] [Google Scholar]
- 95.Siegel R.C., Pinnell S.R., Martin G.R. Cross-linking of collagen and elastin. Properties of lysyl oxidase. Biochemistry. 1970;9(23):4486–4492. doi: 10.1021/bi00825a004. [DOI] [PubMed] [Google Scholar]
- 96.Liu X., Zhao Y., Gao J., Pawlyk B., Starcher B., Spencer J.A., Yanagisawa H., Zuo J., Li T. Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat. Genet. 2004;36(2):178–182. doi: 10.1038/ng1297. [DOI] [PubMed] [Google Scholar]
- 97.Schmelzer C.E.H., Heinz A., Troilo H., Lockhart-Cairns M.P., Jowitt T.A., Marchand M.F., Bidault L., Bignon M., Hedtke T., Barret A., McConnell J.C., Sherratt M.J., Germain S., Hulmes D.J.S., Baldock C., Muller L. Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin. FASEB J. 2019;33:5468–5481. doi: 10.1096/fj.201801860RR. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 98.Jensen S.A., Reinhardt D.P., Gibson M.A., Weiss A.S. Protein interaction studies of MAGP-1 with tropoelastin and fibrillin-1. J. Biol. Chem. 2001;276(43):39661–39666. doi: 10.1074/jbc.M104533200. [DOI] [PubMed] [Google Scholar]
- 99.Craft C.S., Broekelmann T.J., Mecham R.P. Microfibril-associated glycoproteins MAGP-1 and MAGP-2 in disease. Matrix Biol. 2018;71-72:100–111. doi: 10.1016/j.matbio.2018.03.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 100.Trask T.M., Trask B.C., Ritty T.M., Abrams W.R., Rosenbloom J., Mecham R.P. Interaction of tropoelastin with the amino-terminal domains of fibrillin-1 and fibrillin-2 suggests a role for the fibrillins in elastic fiber assembly. J. Biol. Chem. 2000;275(32):24400–24406. doi: 10.1074/jbc.M003665200. [DOI] [PubMed] [Google Scholar]
- 101.Pilecki B., Holm A.T., Schlosser A., Moeller J.B., Wohl A.P., Zuk A.V., Heumuller S.E., Wallis R., Moestrup S.K., Sengle G., Holmskov U., Sorensen G.L. Characterization of microfibrillar-associated protein 4 (MFAP4) as a tropoelastin- and fibrillin-binding protein involved in elastic fiber formation. J. Biol. Chem. 2016;291(3):1103–1114. doi: 10.1074/jbc.M115.681775. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 102.Rock M.J., Cain S.A., Freeman L.J., Morgan A., Mellody K., Marson A., Shuttleworth C.A., Weiss A.S., Kielty C.M. Molecular basis of elastic fiber formation. Critical interactions and a tropoelastin-fibrillin-1 cross-link. J Biol Chem. 2004;279(22):23748–23758. doi: 10.1074/jbc.M400212200. [DOI] [PubMed] [Google Scholar]
- 103.Clarke A.W., Wise S.G., Cain S.A., Kielty C.M., Weiss A.S. Coacervation is promoted by molecular interactions between the PF2 segment of fibrillin-1 and the domain 4 region of tropoelastin. Biochemistry. 2005;44(30):10271–10281. doi: 10.1021/bi050530d. [DOI] [PubMed] [Google Scholar]
- 104.Kanzaki T., Olofsson A., Moren A., Wernstedt C., Hellman U., Miyazono K., Claesson-Welsh L., Heldin C.H. TGF-beta 1 binding protein: a component of the large latent complex of TGF-beta 1 with multiple repeat sequences. Cell. 1990;61(6):1051–1061. doi: 10.1016/0092-8674(90)90069-q. [DOI] [PubMed] [Google Scholar]
- 105.Moren A., Olofsson A., Stenman G., Sahlin P., Kanzaki T., Claesson-Welsh L., ten Dijke P., Miyazono K., Heldin C.H. Identification and characterization of LTBP-2, a novel latent transforming growth factor-beta-binding protein. J. Biol. Chem. 1994;269(51):32469–32478. [PubMed] [Google Scholar]
- 106.Yin W., Smiley E., Germiller J., Mecham R.P., Florer J.B., Wenstrup R.J., Bonadio J. Isolation of a novel latent transforming growth factor-beta binding protein gene (LTBP-3) J. Biol. Chem. 1995;270(17):10147–10160. doi: 10.1074/jbc.270.17.10147. [DOI] [PubMed] [Google Scholar]
- 107.Giltay R., Kostka G., Timpl R. Sequence and expression of a novel member (LTBP-4) of the family of latent transforming growth factor-beta binding proteins. FEBS Lett. 1997;411(2–3):164–168. doi: 10.1016/s0014-5793(97)00685-6. [DOI] [PubMed] [Google Scholar]
- 108.Miyazono K., Olofsson A., Colosetti P., Heldin C.H. A role of the latent TGF-beta 1-binding protein in the assembly and secretion of TGF-beta 1. EMBO J. 1991;10(5):1091–1101. doi: 10.1002/j.1460-2075.1991.tb08049.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109.Saharinen J., Keski-Oja J. Specific sequence motif of 8-Cys repeats of TGF-beta binding proteins, LTBPs, creates a hydrophobic interaction surface for binding of small latent TGF-beta. Mol. Biol. Cell. 2000;11(8):2691–2704. doi: 10.1091/mbc.11.8.2691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110.Dabovic B., Chen Y., Choi J., Vassallo M., Dietz H.C., Ramirez F., von Melchner H., Davis E.C., Rifkin D.B. Dual functions for LTBP in lung development: LTBP-4 independently modulates elastogenesis and TGF-beta activity. J. Cell. Physiol. 2009;219(1):14–22. doi: 10.1002/jcp.21643. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 111.Olofsson A., Ichijo H., Moren A., ten Dijke P., Miyazono K., Heldin C.H. Efficient association of an amino-terminally extended form of human latent transforming growth factor-beta binding protein with the extracellular matrix. J. Biol. Chem. 1995;270(52):31294–31297. doi: 10.1074/jbc.270.52.31294. [DOI] [PubMed] [Google Scholar]
- 112.Miyazono K., Hellman U., Wernstedt C., Heldin C.H. Latent high molecular weight complex of transforming growth factor beta 1. Purification from human platelets and structural characterization. J. Biol. Chem. 1988;263(13):6407–6415. [PubMed] [Google Scholar]
- 113.Saharinen J., Taipale J., Monni O., Keski-Oja J. Identification and characterization of a new latent transforming growth factor-beta-binding protein, LTBP-4. J. Biol. Chem. 1998;273(29):18459–18469. doi: 10.1074/jbc.273.29.18459. [DOI] [PubMed] [Google Scholar]
- 114.Fujikawa Y., Yoshida H., Inoue T., Ohbayashi T., Noda K., von Melchner H., Iwasaka T., Shiojima I., Akama T.O., Nakamura T. Latent TGF-beta binding protein 2 and 4 have essential overlapping functions in microfibril development. Sci. Rep. 2017;7:43714. doi: 10.1038/srep43714. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 115.Dabovic B., Chen Y., Choi J., Davis E.C., Sakai L.Y., Todorovic V., Vassallo M., Zilberberg L., Singh A., Rifkin D.B. Control of lung development by latent TGF-beta binding proteins. J. Cell. Physiol. 2011;226(6):1499–1509. doi: 10.1002/jcp.22479. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116.Zilberberg L., Todorovic V., Dabovic B., Horiguchi M., Courousse T., Sakai L.Y., Rifkin D.B. Specificity of latent TGF-beta binding protein (LTBP) incorporation into matrix: role of fibrillins and fibronectin. J. Cell. Physiol. 2012;227(12):3828–3836. doi: 10.1002/jcp.24094. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117.Dallas S.L., Sivakumar P., Jones C.J., Chen Q., Peters D.M., Mosher D.F., Humphries M.J., Kielty C.M. Fibronectin regulates latent transforming growth factor-beta (TGF beta) by controlling matrix assembly of latent TGF beta-binding protein-1. J. Biol. Chem. 2005;280(19):18871–18880. doi: 10.1074/jbc.M410762200. [DOI] [PubMed] [Google Scholar]
- 118.Fontana L., Chen Y., Prijatelj P., Sakai T., Fassler R., Sakai L.Y., Rifkin D.B. Fibronectin is required for integrin alphavbeta6-mediated activation of latent TGF-beta complexes containing LTBP-1. FASEB J. 2005;19(13):1798–1808. doi: 10.1096/fj.05-4134com. [DOI] [PubMed] [Google Scholar]
- 119.Ono R.N., Sengle G., Charbonneau N.L., Carlberg V., Bachinger H.P., Sasaki T., Lee-Arteaga S., Zilberberg L., Rifkin D.B., Ramirez F., Chu M.L., Sakai L.Y. Latent transforming growth factor beta-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites. J. Biol. Chem. 2009;284(25):16872–16881. doi: 10.1074/jbc.M809348200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 120.Isogai Z., Ono R.N., Ushiro S., Keene D.R., Chen Y., Mazzieri R., Charbonneau N.L., Reinhardt D.P., Rifkin D.B., Sakai L.Y. Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein. J. Biol. Chem. 2003;278(4):2750–2757. doi: 10.1074/jbc.M209256200. [DOI] [PubMed] [Google Scholar]
- 121.Hirani R., Hanssen E., Gibson M.A. LTBP-2 specifically interacts with the amino-terminal region of fibrillin-1 and competes with LTBP-1 for binding to this microfibrillar protein. Matrix Biol. 2007;26(4):213–223. doi: 10.1016/j.matbio.2006.12.006. [DOI] [PubMed] [Google Scholar]
- 122.Troilo H., Steer R., Collins R.F., Kielty C.M., Baldock C. Independent multimerization of Latent TGFbeta Binding Protein-1 stabilized by cross-linking and enhanced by heparan sulfate. Sci. Rep. 2016;6:34347. doi: 10.1038/srep34347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 123.Parsi M.K., Adams J.R., Whitelock J., Gibson M.A. LTBP-2 has multiple heparin/heparan sulfate binding sites. Matrix Biol. 2010;29(5):393–401. doi: 10.1016/j.matbio.2010.03.005. [DOI] [PubMed] [Google Scholar]
- 124.Kantola A.K., Keski-Oja J., Koli K. Fibronectin and heparin binding domains of latent TGF-beta binding protein (LTBP)-4 mediate matrix targeting and cell adhesion. Exp. Cell Res. 2008;314(13):2488–2500. doi: 10.1016/j.yexcr.2008.05.010. [DOI] [PubMed] [Google Scholar]
- 125.Nunes I., Gleizes P.E., Metz C.N., Rifkin D.B. Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta. J. Cell Biol. 1997;136(5):1151–1163. doi: 10.1083/jcb.136.5.1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 126.Verderio E., Gaudry C., Gross S., Smith C., Downes S., Griffin M. Regulation of cell surface tissue transglutaminase: effects on matrix storage of latent transforming growth factor-beta binding protein-1. J. Histochem. Cytochem. 1999;47(11):1417–1432. doi: 10.1177/002215549904701108. [DOI] [PubMed] [Google Scholar]
- 127.Gibson M.A., Hatzinikolas G., Davis E.C., Baker E., Sutherland G.R., Mecham R.P. Bovine latent transforming growth factor beta 1-binding protein 2: molecular cloning, identification of tissue isoforms, and immunolocalization to elastin-associated microfibrils. Mol. Cell. Biol. 1995;15(12):6932–6942. doi: 10.1128/mcb.15.12.6932. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 128.Vehvilainen P., Hyytiainen M., Keski-Oja J. Matrix association of latent TGF-beta binding protein-2 (LTBP-2) is dependent on fibrillin-1. J. Cell. Physiol. 2009;221(3):586–593. doi: 10.1002/jcp.21888. [DOI] [PubMed] [Google Scholar]
- 129.Hirai M., Horiguchi M., Ohbayashi T., Kita T., Chien K.R., Nakamura T. Latent TGF-beta-binding protein 2 binds to DANCE/fibulin-5 and regulates elastic fiber assembly. EMBO J. 2007;26(14):3283–3295. doi: 10.1038/sj.emboj.7601768. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 130.Sideek M.A., Menz C., Parsi M.K., Gibson M.A. LTBP-2 competes with tropoelastin for binding to fibulin-5 and heparin, and is a negative modulator of elastinogenesis. Matrix Biol. 2014;34:114–123. doi: 10.1016/j.matbio.2013.10.007. [DOI] [PubMed] [Google Scholar]
- 131.Penttinen C., Saharinen J., Weikkolainen K., Hyytiainen M., Keski-Oja J. Secretion of human latent TGF-beta-binding protein-3 (LTBP-3) is dependent on co-expression of TGF-beta. J. Cell Sci. 2002;115(Pt 17):3457–3468. doi: 10.1242/jcs.115.17.3457. [DOI] [PubMed] [Google Scholar]
- 132.Chen Y., Dabovic B., Annes J.P., Rifkin D.B. Latent TGF-beta binding protein-3 (LTBP-3) requires binding to TGF-beta for secretion. FEBS Lett. 2002;517(1–3):277–280. doi: 10.1016/s0014-5793(02)02648-0. [DOI] [PubMed] [Google Scholar]
- 133.Noda K., Dabovic B., Takagi K., Inoue T., Horiguchi M., Hirai M., Fujikawa Y., Akama T.O., Kusumoto K., Zilberberg L., Sakai L.Y., Koli K., Naitoh M., von Melchner H., Suzuki S., Rifkin D.B., Nakamura T. Latent TGF-beta binding protein 4 promotes elastic fiber assembly by interacting with fibulin-5. Proc. Natl. Acad. Sci. U. S. A. 2013;110(8):2852–2857. doi: 10.1073/pnas.1215779110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 134.Urban Z., Hucthagowder V., Schurmann N., Todorovic V., Zilberberg L., Choi J., Sens C., Brown C.W., Clark R.D., Holland K.E., Marble M., Sakai L.Y., Dabovic B., Rifkin D.B., Davis E.C. Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Am. J. Hum. Genet. 2009;85(5):593–605. doi: 10.1016/j.ajhg.2009.09.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 135.Sterner-Kock A., Thorey I.S., Koli K., Wempe F., Otte J., Bangsow T., Kuhlmeier K., Kirchner T., Jin S., Keski-Oja J., von Melchner H. Disruption of the gene encoding the latent transforming growth factor-beta binding protein 4 (LTBP-4) causes abnormal lung development, cardiomyopathy, and colorectal cancer. Genes Dev. 2002;16(17):2264–2273. doi: 10.1101/gad.229102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 136.Bultmann-Mellin I., Conradi A., Maul A.C., Dinger K., Wempe F., Wohl A.P., Imhof T., Wunderlich F.T., Bunck A.C., Nakamura T., Koli K., Bloch W., Ghanem A., Heinz A., von Melchner H., Sengle G., Sterner-Kock A. Modeling autosomal recessive cutis laxa type 1C in mice reveals distinct functions for Ltbp-4 isoforms. Dis. Model. Mech. 2015;8(4):403–415. doi: 10.1242/dmm.018960. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 137.Bultmann-Mellin I., Dinger K., Debuschewitz C., Loewe K.M.A., Melcher Y., Plum M.T.W., Appel S., Rappl G., Willenborg S., Schauss A.C., Jungst C., Kruger M., Dressler S., Nakamura T., Wempe F., Alejandre Alcazar M.A., Sterner-Kock A. Role of LTBP4 in alveolarization, angiogenesis, and fibrosis in lungs. Am. J. Phys. Lung Cell. Mol. Phys. 2017;313(4):L687–L698. doi: 10.1152/ajplung.00031.2017. [DOI] [PubMed] [Google Scholar]
- 138.Papke C.L., Yanagisawa H. Fibulin-4 and fibulin-5 in elastogenesis and beyond: insights from mouse and human studies. Matrix Biol. 2014;37:142–149. doi: 10.1016/j.matbio.2014.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 139.El-Hallous E., Sasaki T., Hubmacher D., Getie M., Tiedemann K., Brinckmann J., Batge B., Davis E.C., Reinhardt D.P. Fibrillin-1 interactions with fibulins depend on the first hybrid domain and provide an adaptor function to tropoelastin. J. Biol. Chem. 2007;282(12):8935–8946. doi: 10.1074/jbc.M608204200. [DOI] [PubMed] [Google Scholar]
- 140.Nakamura T., Lozano P.R., Ikeda Y., Iwanaga Y., Hinek A., Minamisawa S., Cheng C.F., Kobuke K., Dalton N., Takada Y., Tashiro K., Ross J., Jr., Honjo T., Chien K.R. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature. 2002;415(6868):171–175. doi: 10.1038/415171a. [DOI] [PubMed] [Google Scholar]
- 141.Yanagisawa H., Davis E.C., Starcher B.C., Ouchi T., Yanagisawa M., Richardson J.A., Olson E.N. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature. 2002;415(6868):168–171. doi: 10.1038/415168a. [DOI] [PubMed] [Google Scholar]
- 142.McLaughlin P.J., Chen Q., Horiguchi M., Starcher B.C., Stanton J.B., Broekelmann T.J., Marmorstein A.D., McKay B., Mecham R., Nakamura T., Marmorstein L.Y. Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. Mol. Cell. Biol. 2006;26(5):1700–1709. doi: 10.1128/MCB.26.5.1700-1709.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 143.Choudhury R., McGovern A., Ridley C., Cain S.A., Baldwin A., Wang M.C., Guo C., Mironov A., Jr., Drymoussi Z., Trump D., Shuttleworth A., Baldock C., Kielty C.M. Differential regulation of elastic fiber formation by fibulin-4 and -5. J. Biol. Chem. 2009;284(36):24553–24567. doi: 10.1074/jbc.M109.019364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 144.Horiguchi M., Inoue T., Ohbayashi T., Hirai M., Noda K., Marmorstein L.Y., Yabe D., Takagi K., Akama T.O., Kita T., Kimura T., Nakamura T. Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase. Proc. Natl. Acad. Sci. 2009;106(45):19029. doi: 10.1073/pnas.0908268106. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145.Hirai M., Ohbayashi T., Horiguchi M., Okawa K., Hagiwara A., Chien K.R., Kita T., Nakamura T. Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo. J. Cell Biol. 2007;176(7):1061–1071. doi: 10.1083/jcb.200611026. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 146.Bultmann-Mellin I., Essers J., van Heijingen P.M., von Melchner H., Sengle G., Sterner-Kock A. Function of Ltbp-4L and fibulin-4 in survival and elastogenesis in mice. Dis. Model. Mech. 2016;9(11):1367–1374. doi: 10.1242/dmm.026005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 147.Ramnath N.W., van de Luijtgaarden K.M., van der Pluijm I., van Nimwegen M., van Heijningen P.M., Swagemakers S.M., van Thiel B.S., Ridwan R.Y., van Vliet N., Vermeij M., Hawinkels L.J., de Munck A., Dzyubachyk O., Meijering E., van der Spek P., Rottier R., Yanagisawa H., Hendriks R.W., Kanaar R., Rouwet E.V., Kleinjan A., Essers J. Extracellular matrix defects in aneurysmal Fibulin-4 mice predispose to lung emphysema. PLoS One. 2014;9(9) doi: 10.1371/journal.pone.0106054. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 148.Colombatti A., Spessotto P., Doliana R., Mongiat M., Bressan G.M., Esposito G. Frontiers in Immunology 2. 2012. The EMILIN/multimerin family. [Google Scholar]
- 149.Schiavinato A., Keene D.R., Wohl A.P., Corallo D., Colombatti A., Wagener R., Paulsson M., Bonaldo P., Sengle G. Targeting of EMILIN-1 and EMILIN-2 to fibrillin microfibrils facilitates their incorporation into the extracellular matrix. J. Investig. Dermatol. 2016;136(6):1150–1160. doi: 10.1016/j.jid.2016.02.021. [DOI] [PubMed] [Google Scholar]
- 150.Danussi C., Petrucco A., Wassermann B., Pivetta E., Modica T.M.E., Belluz L.D., Colombatti A., Spessotto P. EMILIN1-alpha 4/alpha 9 integrin interaction inhibits dermal fibroblast and keratinocyte proliferation. J. Cell Biol. 2011;195(1):131–145. doi: 10.1083/jcb.201008013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 151.Rabajdova M., Urban P., Spakova I., Saksun L., Dudic R., Ostro A., Caprnda M., Kruzliak P., Adamek M., Marekova M. The crucial role of emilin 1 gene expression during progression of tumor growth. J. Cancer Res. Clin. Oncol. 2016;142(11):2397–2402. doi: 10.1007/s00432-016-2226-0. [DOI] [PubMed] [Google Scholar]
- 152.Schiavinato A., Keene D.R., Imhof T., Doliana R., Sasaki T., Sengle G. Scientific Reports 7. 2017. Fibulin-4 deposition requires EMILIN-1 in the extracellular matrix of osteoblasts. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 153.Baldock C., Koster A.J., Ziese U., Rock M.J., Sherratt M.J., Kadler K.E., Shuttleworth C.A., Kielty C.M. The supramolecular organization of fibrillin-rich microfibrils. J. Cell Biol. 2001;152:1045–1056. doi: 10.1083/jcb.152.5.1045. (d PMID: 11238459) [DOI] [PMC free article] [PubMed] [Google Scholar]
- 154.Lu Y., Holmes D.F., Baldock C. Evidence for the intramolecular pleating model of fibrillin microfibril organisation from single particle image analysis. J. Mol. Biol. 2005;349:73–85. doi: 10.1016/j.jmb.2005.03.066. (PMID: 15876369) [DOI] [PubMed] [Google Scholar]