Molecular mechanisms of STIM/Orai communication

Isabella Derler; Isaac Jardin; Christoph Romanin

doi:10.1152/ajpcell.00007.2016

. 2016 Apr 15;310(8):C643–C662. doi: 10.1152/ajpcell.00007.2016

Molecular mechanisms of STIM/Orai communication

Isabella Derler ¹, Isaac Jardin ², Christoph Romanin ^1,^*,^✉

PMCID: PMC4835918 PMID: 26825122

Abstract

Ca²⁺ entry into the cell via store-operated Ca²⁺ release-activated Ca²⁺ (CRAC) channels triggers diverse signaling cascades that affect cellular processes like cell growth, gene regulation, secretion, and cell death. These store-operated Ca²⁺ channels open after depletion of intracellular Ca²⁺ stores, and their main features are fully reconstituted by the two molecular key players: the stromal interaction molecule (STIM) and Orai. STIM represents an endoplasmic reticulum-located Ca²⁺ sensor, while Orai forms a highly Ca²⁺-selective ion channel in the plasma membrane. Functional as well as mutagenesis studies together with structural insights about STIM and Orai proteins provide a molecular picture of the interplay of these two key players in the CRAC signaling cascade. This review focuses on the main experimental advances in the understanding of the STIM1-Orai choreography, thereby establishing a portrait of key mechanistic steps in the CRAC channel signaling cascade. The focus is on the activation of the STIM proteins, the subsequent coupling of STIM1 to Orai1, and the consequent structural rearrangements that gate the Orai channels into the open state to allow Ca²⁺ permeation into the cell.

Keywords: CRAC channel, STIM1, Orai, STIM-Orai interaction, Orai gating

ca²⁺ is a major intracellular messenger in eukaryotic cells. Changes in intracellular Ca²⁺ concentration are required for many physiological processes ranging from fast events like exocytosis to long-term processes like proliferation (13, 14, 74). Store-operated calcium channels (SOCs) constitute the main Ca²⁺ entry pathway into the cell (1, 11, 12, 16, 34, 36, 42, 43, 50, 62, 77, 78, 118, 119, 125, 139, 143, 196) and occur in almost all cell types (3, 11, 12, 16, 144).

While the discovery of store-operated Ca²⁺ ion channels has a long history since the 1970s and 1980s, the molecular players that choreograph store-operated Ca²⁺ entry have only been investigated within the past decade (5, 46, 78, 84, 125, 134, 137, 170, 185). Already in the early 1980s, the idea arose that cells contain cytosolic Ca²⁺ stores, which release Ca²⁺ after stimulation by certain physiological agonists (58, 108, 134, 163). This depletion of internal stores has been supposed to enable external Ca²⁺ to enter the cell, thus triggering diverse signaling cascades that cause, among other processes, secretion, gene transcription, or cell proliferation (19, 47). The most prominent store-operated Ca²⁺ entry pathway is represented by the Ca²⁺ release-activated Ca²⁺ (CRAC) channel (118). Thereby, Ca²⁺ store depletion from the endoplasmic reticulum (ER) is initiated via binding of inositol 1,4,5-trisphosphate (IP₃) to its respective receptor. Upon a drop in ER Ca²⁺ levels through IP₃ receptor-mediated Ca²⁺ release, CRAC channels activate to refill these stores and initiate responses by a drastic increase in cytosolic Ca²⁺ levels (46).

Two proteins, i.e., stromal interaction molecule 1 (STIM1) and Orai1 (also called CRACM1), were revealed only in 2005–6, via function-based genetic screen by systematic RNA interference, as the key components fully reconstituting CRAC channel function (19, 46, 84, 103, 123, 137, 152, 185). In addition, the severe combined immune deficiency (SCID) syndrome, which is accompanied by a defect in CRAC channel function, cleared the way to the discovery of the Orai1 channel protein and its mutant Orai1 R91W, occurring in SCID patients (46).

STIM1 represents the ER-located Ca²⁺-sensing stromal interaction molecule (84, 137, 153, 186), which senses the ER Ca²⁺ content by its luminal EF-hand in the NH₂ terminus. The Orai channel is the plasma membrane (PM) pore-forming subunit of the CRAC channel (46, 84, 128, 170, 178, 181, 185, 186), which is made up of four transmembrane (TM) domains flanked by cytosolic NH₂ and COOH termini (47, 60, 170) and forms highly Ca²⁺-selective pores located in the PM. After Ca²⁺ store depletion, STIM1 multimerizes and redistributes into discrete puncta close to the PM (9, 18, 22, 121, 178). Subsequently, STIM1 couples to and stimulates Orai1, initiating pronounced CRAC currents (110, 111). It has been demonstrated in vitro that these two proteins are indispensable and sufficient to fully restore store-operated Ca²⁺ currents (191).

The discovery of these two proteins has enabled us to obtain a basic understanding of the course of events starting with the release of Ca²⁺ from the ER and finally culminating in Ca²⁺ entry from the extracellular side. A further milestone in the characterization of STIM and Orai proteins was reached in 2012–13 by crystallization of cytosolic fragments of STIM1 (161, 162, 180, 190) and the full-length Orai channel of Drosophila melanogaster (dOrai) (63). Moreover, the structure of a complex of STIM1 and Orai1 COOH-terminal fragments has been resolved by NMR (161). All these structures have provided further resolution of intra- and intermolecular interactions and represent a basis to derive potential conformational changes from the closed to the active state. This review focuses on the molecular mechanisms of STIM1/Orai communication.

STIM and Orai Proteins

STIM proteins.

The STIM protein family includes two members, STIM1 and STIM2 (150), which are both expressed in the ER (84, 95, 151, 186). A lower amount has also been detected in the PM, which is, however, not necessarily required for CRAC channel activation (2, 18, 95). The two isoforms are closely related and share ∼61% sequence identity (18). Among metazoans, from Caenorhabditis elegans and Drosophila to Homo sapiens, STIM proteins are highly conserved (27).

STIM proteins (Fig. 1) are single TM proteins with an NH₂-terminal portion including the Ca²⁺-sensing domain localized within the ER lumen and a long cytosolic strand, which couples to Orai channels in the PM. The STIM NH₂ and COOH termini are separated by an ∼20-amino acid (aa) TM region (18, 84, 137) (Fig. 1A). The NH₂-terminal portion is well conserved from worms and flies to humans, while the COOH-terminal portions are rather divergent among different species (20). The variety of STIM proteins is further extended by diverse splice variants like STIM1L (30) and a STIM2 splice variant (STIM2β, STIM2.1) (104, 136).

The Ca²⁺-sensing domain is formed by the EF-hand and sterile-α-motif (SAM) domain (Fig. 1A), which display distinct properties in STIM1 and STIM2 (162, 190). Upon store depletion, the STIM EF-hand loses Ca²⁺ and alters its communication with the SAM domain (190), which represents the initial step in the CRAC signaling cascade. This signal is transmitted to the cytosolic portion and finally transforms STIM1 into its active conformation.

The STIM1 TM domain (aa 214–233; Fig. 1A) has been recently reported to undergo conformational changes from a potential closed state to the open state (92), thus contributing to the transmission of the stimulatory signal from the luminal side to the COOH terminus. This TM domain contains three small and highly flexible glycines at positions 223, 225, and 226 (56, 92, 177) potentially involved in close helix-helix packing or the introduction of kinks (38).

The STIM1 cytosolic domain (Fig. 1A) includes the essential site(s) for coupling to Orai1 (63, 64, 111). It consists of three conserved cytosolic coiled-coil (CC) domains (aa: C1 233–343, CC2 353–388, CC3_ext 400–450) followed by the CRAC modulatory domain (aa475–483), the COOH-terminal inhibitory domain (CTID, aa447–530), the serine/proline (Ser/Pro)-rich region, a Thr-Arg-Ile-Pro (TRIP) sequence, and the lysine-rich region at the very end of the COOH terminus (56, 57). On the basis of structural predictions, the 110-residue-long CC1 can be subdivided into three α-helical regions (aa: CC1_α1 238–271, CC1_α2 278–304, CC1_α3 308–337) (150, 161, 180). A recent crystal structure of a STIM1 COOH-terminal fragment (SOAR aa344–442), representing the minimal Orai activating fragment and including CC2 and CC3, has revealed four separate regions (Fig. 1A), i.e., Sα1 (aa345–391), Sα2 (aa393–398), Sα3 (aa400–403), and Sα4 (aa409–437) (180). STIM1 and STIM2 display significant differences in their COOH-terminal portion, while the CC domains are well conserved (56). The SOAR/CAD/Ccb9 (71, 121, 183) fragment (Fig. 1A) is almost fully conserved among STIM1 and STIM2; however, STIM1/2 exhibit distinct functions, especially due to the nonconserved residue F394 in STIM1 corresponding to L485 in STIM2 (173).

Structural insights into STIM (Fig. 1A) have been obtained from isolated ER-luminal domains of both STIM1 and STIM2 with Ca²⁺ bound to the EF-hand via NMR (190), and a STIM1 COOH-terminal, SOAR-like, fragment (aa354–444) via X-ray resolution (29) (Fig. 1A). In addition, the NMR structure of a SOAR overlapping fragment (aa312–387) has been obtained in the unbound (Fig. 1A) as well as the Orai1 COOH terminus-bound state (161). The crystal structure of the SOAR fragment has revealed a dimeric, parallel arrangement of two monomers resulting in an overall V-shaped structure (Fig. 1B). The structure of each monomer resembles that of a capital letter “R,” formed by the four helices Sα1–Sα4 (180). The NMR structure of STIM1 aa312–387, including CC1α3 and CC2, displays a bend of almost 180° between these two helical domains (Fig. 1A). Two such fragments assemble as dimers in an antiparallel manner (Fig. 1B) (161). These two structures exhibit large differences, and substantial structural changes would be required to transform one form into the other.

Intra- and intermolecular interactions within and between STIM1 proteins control the activation status of STIM1 (Fig. 1C, see below) (44, 72, 92, 110, 180, 193). Upon store depletion STIM1 COOH terminus couples to Orai channels, thus mediating CRAC current activation (80, 111).

Orai proteins.

Orai proteins (Fig. 2) represent Ca²⁺-selective ion channels in the PM including three highly conserved homologs, termed Orai1-3 (15, 46, 170, 170). Each Orai monomer contains four TM segments linked via one intracellular and two extracellular loops and cytosolic NH₂ and COOH termini (68, 105, 124) (Fig. 2A). The TM regions share ∼81–87% pairwise sequence identity, whereas TM1 is fully conserved among Orai proteins. The cytosolic strands, extra- and intracellular loops are less conserved, except for segments involved in direct binding of STIM1 (58). Major structural differences are found in extracellular loop3, which is much longer in Orai3, as well as in the cytosolic NH₂ and COOH termini, which share 34% and 46% sequence homology, respectively (148). Both cytosolic strands of Orai are required for functional coupling to STIM1 (35, 80, 100, 111, 115, 121, 189). STIM1-mediated Orai currents display strongly inward-rectifying Ca²⁺ currents and a low single-channel conductance similar to what has been reported for endogenous CRAC channels (86).

For a long time it has been thought that four Orai subunits form the functional channel (31, 34, 93, 96, 105, 124); however, in 2012 the crystal structure of the dOrai channel put forward the idea that the channel may be composed of six subunits (Fig. 2B) (63). A closer look further reveals, besides the sixfold central axis of symmetry along the pore, an overall threefold symmetry, as dOrai monomers are arranged as three dimers within the hexameric complex (63). The ion pore, located in the center of the hexamer, is surrounded by three rings of TM domains (Fig. 2B). The first ring is formed by TM1 of each subunit and forms the pore, the second ring includes TM2 and TM3, and the third ring is formed by TM4 (63). Analogous to dOrai, the Orai1 proximal NH₂ terminus likely forms an α-helical extension of TM1 of ∼20 Å (Fig. 2C), the so-called extended TM Orai1 NH₂-terminal (ETON) region (35). Furthermore, TM2 and TM3 have been found to extend by a few helical turns into the cytosol (63). They are linked by a small flexible portion, loop2, that has not been resolved in the X-ray structure. Moreover, the structural resolution of the two extracellular loops is still lacking. A combination of molecular modeling and molecular dynamics (MD) simulations suggests the highest flexibility is in loop3 (51). Interestingly, the Orai COOH terminus is connected to TM4 via a highly conserved hinge region and couples to the COOH terminus of the adjacent Orai subunit in an antiparallel manner. Hence, the Orai hexamer is built up from three dimers, each with antiparallel crossing COOH termini (110, 111, 113).

Detailed Presentation of Steps Within STIM1/Orai Signaling Cascade

STIM1 in the resting state.

Cells in the resting state display a homogeneous distribution of STIM1 proteins, which move rapidly along the microtubules (149). In accordance with this, Baba et al. (6) have reported dynamic and constitutive movement of STIM1 before store depletion, which is governed by CC regions and the Ser/Pro-rich domain. The diffusion speed is in the range of 0.1 μm²/s, which is slow compared with other single-pass membrane proteins. Deletion of the cytosolic domains (STIM1 ΔC = STIM1 aa1–237) results in a twofold-increased diffusion speed comparable to other single-pass membrane proteins (28), suggesting that STIM1 proteins are slowed upon the interaction of their COOH termini.

The structure of full-length STIM1 in the resting state is still elusive. Nonetheless, the EF-SAM domains of STIM1 and STIM2 have been structurally well resolved in the Ca²⁺-bound state (190). As long as the stores are full, the EF-SAM domain forms a stable and compact monomer with a mainly α-helical structure (Fig. 1C) (162, 190). It is composed of a canonical and a noncanonical EF-hand that are followed by the SAM domain (158, 160, 162). Ca²⁺ is bound to the EF-hand via negatively charged aspartates and glutamates. The noncanonical EF-hand does not bind Ca²⁺ but stabilizes the monomeric state and the SAM domain (159, 190). Mechanistically, the EF-hands of two monomers form a hydrophobic cleft that binds to hydrophobic residues in the SAM domain in order to stabilize the resting state of the EF-SAM structure.

While STIM1 is inactive in the cell resting state and responds only to large drops in luminal Ca²⁺ levels, STIM2 is partially active already at smaller changes in luminal Ca²⁺ (17). This distinct behavior of the two STIM isoforms in response to cytosolic Ca²⁺ levels is mirrored in the properties and a distinct structural stability of their EF-SAM regions. The canonical EF-hand of STIM1 possesses a higher Ca²⁺ affinity than that of STIM2, while the hydrophobic and electrostatic interactions of the EF-hands and SAM are less stable in STIM1 compared with those in STIM2 (159, 190). Thus the response of STIM1 occurs in a very fast manner, but only to larger drops in ER Ca²⁺ concentrations, while STIM2 activates at smaller changes in Ca²⁺ levels, yet in a slower manner (162, 190).

The luminal EF-SAM domain is followed by a single TM domain that has just recently been reported (92) to contribute to the switch between the inactive and active states of STIM1. As shown by studies of a STIM1 gain-of-function mutant, C227W, STIM1 TM regions are supposed to cross each other with a certain angle that decreases upon store depletion. In the resting state (Fig. 1C), residues in the more COOH-terminal portion of the TM (aa221–232) have been shown to interact, while those in the NH₂-terminal portion are positioned farther apart from each other (92).

Besides the luminal as well as TM domains, STIM1 cytosolic portions also control the resting state of STIM proteins. STIM1 proteins are assumed to form dimers before store depletion, since they interact with each other and isolated STIM1 fragments mostly occur as dimers (6, 64, 109, 176, 191, 193). This STIM1 dimer interaction involves the COOH-terminal regions, i.e., CC1 and CAD/SOAR. While CC1 supports dimerization, CAD/SOAR is dominant in mediating dimerization (28). Based on the crystal structure of SOAR (180), the dimeric interaction of SOAR monomers is mediated via several hydrophobic and hydrogen bond interactions (Fig. 1B). Specifically, NH₂-terminal residues of one monomer (T354, L351, W350, L347) couple to COOH-terminal residues of the second monomer (R429, W430, T433, L436) (180) (Fig. 1B, left). An NMR STIM1 structure further suggests dimeric coupling via overlapping domains of CC1_α3 (E320-A331) as well as CC2 (H355-A369) (Fig. 1B, right) (161). A cytosolic STIM1 homomerization domain (SHD) has been assigned to the segment ∼421–450, an extended portion of CC3 (109). Deletion of the SHD in a short STIM1 COOH-terminal fragment, the so-called Orai1 activating STIM1 fragment (OASF; Fig. 1A), results in substantially reduced homomerization (109).

The inactive, tight state of STIM1 (Fig. 1C) is maintained via an intramolecular clamp established via specific interactions of CC1 and CAD/SOAR. Originally, Korzeniowski et al. (72) reported an electrostatic clamp between a highly conserved acidic region in CC1 (E318/319/320/322A) and a basic region in CC2 (K382/384/385/384A). However, later reports have demonstrated that these regions are not located in close proximity (180, 193). Nevertheless, the hypothesis of an inhibitory clamp has been further supported by recent studies (110, 193), based on high Förster resonance energy transfer (FRET) or luminescence resonance energy transfer (LRET) values of STIM1 fragments labeled on both sides, which is reduced in the presence of Orai1. This intramolecular clamp is formed between CC1_α1 and CC3 in line with Reference 92 and involves several residues as derived below.

The substitution of L248S, L251S, or L258S in CC1_α1 and L416S or L423S in CC3 leads to a decrease of FRET as determined from a double-labeled STIM1 COOH-terminal OASF fragment, suggesting that these residues retain STIM1 in a tight, inactive conformation (110, 193). The crystal structure of C. elegans SOAR extended by CC1 together with functional studies has suggested that the amino acid stretch aa308–337 in CC1_α3, which includes the residues E318/319/320/322 (72), functions as an inhibitory helix, as slightly constitutive activation of Orai1 has been observed upon deletion of aa310–337 in STIM1 (180). In addition, residues of CC2 (A369) and CC3 (L416, L423) are, because of their close proximity in the X-ray structure, supposed to be involved in intramolecular interactions (180). The R426L mutation in CC3 has been shown to promote the tight conformation of STIM1 fragments (44, 110). Moreover, Y316 in CC1_α3 contributes to the maintenance of STIM1 in the inactive state (182). Hence, residues in both CC1_α1 as well as CC1_α3 and CC3 helices contribute to the inhibitory clamp for fixing the STIM1 tight, inactive state (Fig. 1C), while potential interaction sites on CC2 and CC3 of CAD/SOAR remain elusive so far. Recently, it has been suggested that coiled-coil interactions of L258 and L261 of CC1_α1 with V419 and L416 of CC3 maintain the inhibitory clamp (92); however, this assumption still requires experimental validation.

Activation of STIM1 via Signal Transduction of STIM1 NH₂ Terminus to Its COOH Terminus

After ER store depletion, the homogeneous distribution of overexpressed fluorescence-tagged STIM1 proteins changes into punctae localized at the ER-PM junctions (84, 91, 137, 178). In line with FRET measurements, STIM1 proteins form stable oligomers (28, 83, 111), which leads to slowed movement along the microtubules (28, 85). Store-operated puncta formation is determined by both luminal as well as cytoplasmic STIM1 domains (28). Furthermore, STIM1 promotes the formation of ER-PM junctions by binding to the microtubule tip attachment protein EB1 (53). Other proteins like one of the extended synaptotagmin family, ESyt1, which interacts with phosphatidylinositol 4,5-bisphosphate (PIP₂), and junctate, already localized at ER-PM junctions, have been reported to support the formation of ER-PM contacts (24, 52, 154, 167, 168). Additionally, an ER-resident protein, STIMATE (TMEM110), facilitates and enhances STIM1 puncta formation at ER-PM junctions because of coupling of the two proteins (69, 135). Knockdown of STIMATE results in reduced puncta formation that can be partially reversed by artificially restored junctions via Ist2, an ER-membrane protein that recruits ER to the PM (69, 135).

Loss of Ca²⁺ binding at the luminal EF-SAM domain triggers conformational changes in the NH₂ terminus that are transmitted via the TM domain to the COOH terminus, finally culminating in the interaction with and activation of Orai channels (Fig. 3) (132). Based on an elegant study by Luik et al. (90) in which artificial luminal cross-linking of STIM1 was utilized, it is suggested that initial di- and/or oligomerization on the luminal side of STIM1 represents the first step in the activation cascade of STIM1.

Fig. 3. — A and B: cartoons representing a hypothetical model for the coupling of STIM1 and Orai1. After store depletion, STIM1 proteins lose the Ca²⁺ bound to the luminal EF-hand and undergo a conformational change from the inactive, tight state (A) to the active, extended state (B). Thereby, the crossing angle of the TM helices alters and the inhibitory, intramolecular clamp between CC1_α1 and CC3 is released. C: extension of STIM1 proteins leads to the interaction with Orai1, is accompanied by oligomerization of STIM1 proteins to larger aggregates than dimers, and involves the CC3 domains. *Inset* depicts intermolecular interactions between the STIM1 CC1α3-CC2 and Orai1 COOH terminus in the STIM1-Orai1 association pocket. PM, plasma membrane.

Initial structural changes upon loss of Ca²⁺ at the luminal side are accompanied by an unfolding of the EF-SAM domain, based on structural and biochemical studies of the isolated STIM1 EF-SAM domain (190). Thereby the EF-SAM domain exposes hydrophobic surfaces that trigger the aggregation of STIM proteins into dimers and higher-order oligomers in solution (159, 190). In line with this, STIM1 deletion mutants lacking the whole COOH terminus have been shown to multimerize upon Ca²⁺ store depletion (28). The isolated EF-SAM domains of STIM1 and STIM2 exhibit distinct K_Ds for Ca²⁺ binding of ∼200 and 500 μM (190), respectively. The calculated Hill coefficient for the luminal domain of STIM1 under low ER Ca²⁺ concentrations is ∼4, which is rather high and in accordance with a potential multimeric assembly (90). Oligomerization upon loss of Ca²⁺ binding is in accordance with constitutive puncta formation of STIM1 EF-hand mutants (D76A, E87A) lacking Ca²⁺ binding as well as increased aggregation of STIM1 peptides in solution (153, 186). Further FRET studies have revealed an increase in the homomeric interaction between STIM1 proteins after store depletion that is decreased upon store refilling (83, 111). STIM1 oligomerization has been shown to occur before STIM1-Orai1 coupling (83).

Structural changes at the luminal side are supposed to trigger conformational rearrangements in the STIM1 TM domain. This assumption is based on recent studies (92) that report mutation of residues (I220, C227) in the TM region that induce constitutive activity of STIM1. These findings together with NMR and LRET studies have led the authors to suppose that store depletion decreases the crossing angle of interacting TM regions, thereby bringing the NH₂-terminal halves (aa 214–220) closer together (Fig. 3B) (92). These novel findings may change the understanding of increased FRET values determined from NH₂-terminally fluorescence-labeled STIM1 upon store depletion, which has so far been interpreted as STIM1 oligomerization. Alternatively, enhanced FRET may also result from closer proximity of luminal NH₂ termini within a STIM1 dimer upon store depletion (132), which still requires further evaluation.

Finally, the STIM1 activating signal initiated at the luminal site is transmitted via the TM domain to STIM1 COOH terminus, resulting in further conformational changes accompanied by oligomerization (Fig. 3). In particular, the STIM1 COOH-terminal CAD/SOAR domain represents an essential determinant for STIM1 oligomerization (28). Serial COOH-terminal STIM1 truncation mutants reveal that CC1 alone is unable to stabilize an oligomeric complex, while in the presence of CAD/SOAR normal STIM1 response to store depletion is obtained (28). CC2 and CC3_ext within CAD/SOAR are supposed to play the dominant role in establishing the oligomeric state after store depletion, in line with the reported role of SHD (109) as well as observed puncta formation by an ER-targeted CAD/SOAR or CC3_ext aa388–449 domain (44). Reduced homomerization upon deletion of SHD is accompanied by abolished activation of Orai1 channels in patch-clamp recordings (109). Multiple important roles of CC3 could be further derived from the loss-of-function mutation R429C therein. This mutation allows STIM1 to transit from the closed to the open state; however, it impairs the formation of functional STIM1 higher-order oligomers and binding to Orai1 (98).

In the active state the inhibitory clamp in the STIM1 COOH-terminal portion is released, switching STIM1 from its tight, inactive state to its extended, active state (Fig. 3, A and B). FRET/LRET studies employing STIM1 fragments labeled on both sides have revealed a reduction of intramolecular FRET upon binding to Orai1 or substitution of specific residues (L248S, L251S, L258S, or the deletion of CC1) (110, 193). The release of the inhibitory clamp by these mutations is further supported by studies with ER-targeted mutated CC1 domains that lose their ability to interact with SOAR/CAD (44, 92). Furthermore, while CC1 occurs as a monomer in solution and binds to CAD, artificially cross-linked CC1 fragments form dimers that exhibit impaired interaction with CAD/SOAR (193), compatible with a di-/homomerization of the CC1 region contributing to the switch into an extended conformation (193). These results suggest that STIM1 COOH terminus adopts an extended form in the active state for exposure of CAD/SOAR and interaction with Orai1 (Fig. 3C). STIMATE has been reported to promote the conformational switch via coupling to CC1, thus perturbing CC1-CAD/SOAR interaction (69). Our recent study (44) additionally reveals a slight, destabilizing impact for the CC1_α2 domain in STIM1, which is drastically enhanced by the R304W mutation therein, which fully activates STIM1 without store depletion and is associated with the Stormorken syndrome (106, 107, 114). As the CC1 region plays an important role in keeping STIM1 in the inactive state (110, 193), the disease-related R304W mutation is likely to disturb the resting, tight STIM1 conformation, promoting the switch into the extended, activated form.

A highly conserved region COOH terminal to SOAR overlapping with CC3_ext, STIM1 (447–530), has been termed the COOH-terminal inhibitory domain (CTID; see Fig. 1A), as mutations within this region caused constitutive, store-independent clustering of STIM1 and activation of Orai1 (67). This region is involved in the interplay with SARAF (23), as explained in detail in Inactivation of Orai Channels.

The rear portion of STIM COOH terminus includes domains possessing a regulatory impact on the STIM/Orai interplay. Here, a Ser/Pro-rich region, a TRIP sequence, as well as a lysine-rich region play a significant role.

The Ser/Pro-rich region as well as the TRIP sequence (see Fig. 1A) located close to each other at the end of the STIM1 COOH terminus control the binding of STIM1 to microtubuli. The first includes phosphorylation sites Ser575, Ser608, and Ser621, which represent target sites for extracellular signal-regulated kinases 1/2 (ERK1/2) (126). These residues modulate STIM1-Orai signaling, as their mutation results in reduced Ca²⁺ entry as well as diminished STIM1-Orai1 coupling (126). The closely located TRIP sequence, encompassing aa642–645 in STIM1 COOH terminus (127), couples to the microtubule plus-end regulator EB1 (53, 165). Mutation of the phosphorylation sites has been also shown to regulate binding to EB1 (127), in line with reports that phosphorylation sites in the vicinity of this TRIP sequence bind to EB1 (165, 174, 195). Mechanistically, Pozo-Guisado et al. (127) have supposed that store depletion activates ERK1/2, which phosphorylates STIM1, thus triggering dissociation from EB1. This allows STIM1 multimerization and coupling to Orai1, while upon store refilling STIM1-EB1 binding avoids a prolonged active state of the STIM1/Orai1 complex.

Puncta formation of STIM proteins is further controlled by a lysine-rich region at the very end of the STIM1 protein, as truncation of the lysin-rich region impaired puncta formation while oligomerization was still preserved (83). This STIM1 COOH-terminal polybasic region represents a PIP₂ binding domain (83). STIM2 contains an even larger lysine-rich domain and exhibits binding to PIP₂ (41). A decrease in PIP₂ levels has been demonstrated to affect puncta formation of STIM1-Orai1 cluster, stabilization of STIM1-PM interactions, and targeting of STIM1 to ER-PM junctions (26, 73, 172). Thus it has been hypothesized that the lysine-rich region couples ER-resident STIM1 to PM-PIP₂, thereby enhancing the amount of STIM proteins in ER-PM junctions. Furthermore, septins that bind PIP₂ have been shown to facilitate efficient STIM1-Orai1 communication (147).

In summary, while the inactive, tight state of STIM1 is controlled by an autoinhibitory interaction of CC1 with CAD/SOAR, the active, extended state of STIM1 is reached by release of this inhibitory clamp supported by CC1 di-/oligomerization and resulting in the exposure of CAD/SOAR for interaction with Orai1. The accumulation of STIM1 proteins in the ER-PM junctions and their oligomerization are further modulated by additional regulatory proteins.

Coupling of STIM1 to Orai1

Activation of STIM1 leads finally to its coupling to Orai1, allowing Ca²⁺ entry into the cell. In the following the main interaction sites of the two molecular key components of the CRAC machinery are presented.

STIM1 COOH-terminal regions.

Overexpression of the STIM1 COOH terminus (aa233–685) has been shown to be sufficient for CRAC channel activation (44, 64, 111). Furthermore, NH₂- and COOH-terminal deletions of STIM1 COOH terminus have revealed a minimal STIM1 COOH-terminal fragment [OASF (aa233–450), CAD (aa342–448), SOAR (aa344–442), and Ccb9 (a339–444)] that is sufficient to activate Orai channels (71, 109, 121, 183). All these fragments (see Fig. 1A) include the CC2 (aa353–388) and CC3_ext (aa400–450) regions, encompassing an Orai coupling and activating domain as well as the SHD (aa421–450) (109). Although the CAD/SOAR domains of STIM1 and STIM2 share ∼80% sequence identity, they possess distinct functional properties. While CAD/SOAR of STIM1 couples strongly to Orai1 and induces robust constitutive activity, that of STIM2 has revealed only weak association with Orai1 and marginal constitutive activity. The residue F394 in STIM1 has been determined as crucial for those functional differences, as the STIM1 F394L mutant, containing the corresponding STIM2 residue, exhibits reduced coupling to Orai1 (173).

CAD has been reported to interact directly with Orai1 (121). A strong CAD interaction has been detected with the Orai1 COOH terminus, while it interacts to a weaker extent with Orai1 NH₂ terminus, in line with Reference 35. In contrast, Orai1 loop2 has not been observed to interact with CAD (121).

A recent NMR structure (161) has drawn a first picture of how STIM1 COOH terminus potentially interacts with Orai1 COOH termini (Fig. 3C). Here, two STIM1 COOH-terminal fragments (aa312–387), including CC1_α3 and CC2, bind in an antiparallel manner to two antiparallel-oriented Orai COOH termini, which fits well with their orientation in the dOrai crystal structure. Critical residues of this STIM1 fragment (Fig. 3C) involved in the interaction with Orai1 COOH terminus (aa272–292) to form the STIM1-Orai1 association pocket (SOAP) represent L347, L351 from the NH₂-terminal side of one CC2 and Y362, L373, A376 from the COOH-terminal side of the other CC2′ fragment together with a cluster of positively charged amino acids, K382, K384, K385, and K386, providing electrostatic complementarity. Within this predominantly hydrophobic groove, side chains from the Orai1 COOH terminus including L273 and L276 pack against opposite faces of the SOAP (Fig. 3C). In line with this, mutation of L347, L351, L373, and A376 within STIM1 has already been reported to functionally disrupt the communication with Orai1 channels (48). Neutralization of the STIM1 positively charged lysine residues in the cluster has been shown to impair coupling to and activation of Orai1 (21, 72, 180). Thus the interaction of STIM1 COOH terminus with Orai1 COOH terminus is structurally well resolved and consistent with the functional effects of mutations within SOAP, while the relevant residues within STIM1 involved in coupling to the Orai1 NH₂ terminus are poorly defined. Recently, the critical residue in the CC2-CC3 linker of the CAD/SOAR domain of STIM1, i.e., F394 (see Fig. 1B), determining the extent of CAD/SOAR coupling to Orai1, has been suggested to interact with exposed leucines in the ETON region of Orai1 to open the channel (173). Its mutation F394H results in loss of coupling to and activation of Orai1 (173); however, a direct binding of STIM1 to the Orai1 NH₂ terminus in the intact channel has not yet been demonstrated. This failure of STIM1 binding may be caused by the weaker affinity to or occlusion of the Orai1 NH₂-terminal binding site, as long as the channel resides in a state without STIM1 bound to the COOH terminus.

Two splice variants of STIM, exhibiting alterations in the COOH-terminal sequence, have been reported to alter coupling to Orai1. The alternatively spliced long variant of STIM1, STIM1L, which is most prominently expressed in muscle, includes an extra stretch of 106 residues in the STIM1 cytosolic domain after the CC3 region (30). The amino acid stretch inserted in STIM1L represents an actin-binding domain that results in permanent cluster formation, thus allowing immediate SOCE activation (30). Another study in a different cell system found STIM1L to form permanent, yet smaller, ER-PM clusters; however, Orai1 channels were not activated faster but with similar kinetics and to the maximal extent as with wild-type STIM1(141).

A STIM2 splice variant (STIM2β, STIM2.1) contains a highly conserved stretch of eight residues within the CAD/SOAR domain, resulting in inhibitory properties of this splice variant (104, 136). STIM2β by itself is unable to bind to Orai1; however, it couples to Orai1 upon heterodimerization with STIM1 or STIM2 and blocks store-operated currents (136).

Orai1 COOH terminus.

The Orai COOH terminus forms the cytosolic extension of TM4 and is connected via a highly conserved hinge (aa261–265) to TM4 (see Fig. 2B) (63). Crossing COOH termini of an Orai dimer form an angle of 152° based on the dOrai crystal structure. Early colocalization and FRET studies have already revealed the Orai1 COOH terminus as indispensable for the coupling to STIM1 (80, 111, 121). Structural predictions suggest that Orai COOH termini form coiled-coil regions, known as typical structural motifs involved in homo- as well as heteromeric protein-protein interactions (97), where the probability for a coiled-coil region is 15- to 17-fold increased for Orai2 and Orai3 compared with that of Orai1 (48). In accordance, single-point mutations within Orai1 COOH terminus (L273S/D, L276S) are sufficient to disrupt the communication with STIM1 (48, 111). The structural resolution of the SOAP complex has clearly confirmed the importance of L273 and L276 as hydrophobic residues relevant for the interaction with STIM1 (161). In contrast to Orai1, double-point mutations were required in Orai2 or Orai3 COOH terminus to fully disrupt coupling to STIM1 (48). Zhang et al. (187) have reported constitutive coupling of STIM1 to Orai3, but not to Orai1, without store depletion, despite comparable activation kinetics. This constitutive coupling may depend on the strength of the Orai COOH-terminal coiled-coil region, which still needs to be examined. Besides L273 and L276, further residues R281, L286, and R289 within the Orai1 COOH terminus are involved in the interaction with STIM1 COOH-terminal SOAP (Fig. 3C) (161). In line with this, adjacent residues predicted not to interact with STIM1 have no effect on STIM1 activation (161).

Strikingly, the hexameric dOrai crystal structure has revealed that L273 and L276 are also involved in COOH-terminal dimerization of each Orai dimer (63). It has been shown experimentally that the hydrophobic interactions of L273/L276 are essential for channel gating, as their substitution to less hydrophobic residues results in loss of Orai1 function (117). Cysteine cross-linking of the COOH terminus pairs at those positions (L273C, L276C) impairs STIM1 binding, which could be rapidly reversed upon disulfide break (166), in line with their critical role in the Orai1 activation process.

The hinge connecting the COOH terminus to TM4 is crucial for establishing the correct conformation of Orai1 COOH termini for coupling to STIM1, as mutations therein affect STIM1 binding and CRAC activation negatively (117, 166). STIM1 binding to Orai1 hinge mutants is significantly reduced compared with wild type but only fully abolished upon additional Orai1 COOH terminus mutation (117), suggesting that the hinge brings the COOH termini in the best position required for accurate STIM1 binding.

The NMR structure of the STIM1 fragment coupled to antiparallel-oriented Orai1 COOH termini has revealed an angle of 136° in contrast to the angle of 152° of the crossing COOH termini in the dOrai crystal structure. These distinct angles may result either from different experimental procedures or from a conformational difference between dOrai and human Orai1. However, it is also likely that the angle of 136° mirrors the dimerization angle in the active state, while 152° displays the crossing angle of Orai COOH termini in the closed state. Alternatively, Hou et al. (63) have suggested a more straightened TM4-COOH terminus connection for Orai1 in the active state upon bridging of NH₂ and COOH termini via STIM1.

Orai1 NH₂ terminus.

Besides the Orai1 COOH terminus, the Orai1 NH₂ terminus also functions as a STIM1 binding partner, even if to a weaker extent than the COOH terminus (35, 121). Relevant binding residues are included in the conserved ETON region (aa73–90) forming the elongated extension of TM1 into the cytosol (see Fig. 2C). A truncation of the NH₂ terminus up to aa72 leaves the channel fully active (35, 100), while upon deletion up to aa74/75 activation via STIM1 or STIM1 cytosolic fragments occurs only to a half-maximal extent and truncation up to aa76 or beyond completely abolishes Orai1 current activation (35). Specific mutations within the ETON region such as the paired L74/W76 (35), L74/L79/L81/L86 substitutions (173), or R83/K87 (35) as well as K85E (87) result in complete loss of coupling as well as activation of the Orai1 channel by STIM1.

Positively charged residues close to TM1 provide in addition to a STIM1 binding site an electrostatic barrier as well as stabilization of the elongated pore (35). Hence, almost the whole ETON region functions as binding interface for the Orai1 interaction with STIM1 and additionally provides electrostatic gating elements to fine-tune the shape of the elongated pore (138).

The ETON region is fully conserved among Orai proteins. Intriguingly, store-operated activation of Orai3 is still retained with more extensive truncations that already abolish Orai1 function. (10, 35) Thus STIM1-mediated Orai3 activation potentially involves further structures that compensate for the extensive NH₂-terminal deletions, the location of which still remains to be resolved.

Although various residues in the Orai1 ETON region have been identified as indispensable for coupling to STIM1, a clear picture of the NH₂-terminal binding pocket for STIM1 is still missing.

Both Orai1 NH₂ and COOH Termini Together Determine STIM1-Mediated Activation and Gating

The above-described resolution of STIM1/Orai1 interaction domains reveals that gating of Orai channels into the open state is established via coupling of STIM1 COOH terminus to specific residues in both Orai1 NH₂ and COOH termini. The presence of only one functional cytosolic strand is not sufficient to allow activation via STIM1, as the deletion or mutation of either the NH₂ or the COOH terminus leads to loss of Orai function (35, 100, 115, 117). Upon disruption of the Orai COOH-terminal binding sites, interaction with full-length STIM1 or STIM1 fragments is completely abolished (80, 111). In contrast, an impaired NH₂-terminal binding site still allows partial coupling of STIM1 with Orai1, very likely via its COOH terminus, although functionality is lost (32, 111). These results together with biochemical binding studies of cytosolic fragments (121) suggest the Orai1 COOH terminus as the stronger binding site compared with the NH₂ terminus. Moreover, all these results indicate that Orai1 NH₂ terminus contributes to gating (35, 111, 138). Hence, both cytosolic strands are indispensable for Orai activation; however, the question remains of how STIM1 attaches to the binding sites of the Orai channels, enabling their activation. One might hypothesize that STIM1 couples initially to the COOH terminus, because of their stronger binding affinity, and subsequently to the NH₂ terminus. Potentially, activation of Orai1 channels occurs via a bridging of Orai1 NH₂ as well as COOH terminus that is most likely accomplished by the CAD/SOAR domain. It may be further assumed that STIM1 binding to the Orai COOH terminus, in addition to a simple anchoring, also involves rearrangements in the TM4 extensions that facilitates concomitant interaction of CAD/SOAR with Orai1 NH₂ terminus.

Recent studies (100, 115, 117) have examined the requirement of STIM1 interaction with both Orai1 NH₂ and COOH termini, utilizing local enrichment of STIM1 COOH terminus by tethering CAD fragments to either the NH₂ or the COOH terminus. The deletion mutants Orai1-Δ1–76 and Orai1-Δ276–301, which are nonfunctional upon stimulation with STIM1, remain partially active in the presence of tethered CAD (117). Nevertheless, a minimal portion of Orai1 NH₂ terminus (aa77–90) and COOH terminus (aa267–275) is still required also for preserved activation via tethered STIM1, as evident from loss of function of Orai1-Δ1–77 or Orai1-Δ273–301 tethered to CAD/SOAR. Single-point mutations either in NH₂ or COOH terminus impairing function upon stimulation via cytosolic STIM1 fragments do not inhibit activation of analog Orai1 mutants with tethered STIM1 fragments (115). Thus the local attachment of CAD/SOAR here apparently circumvents the requirement of two functional cytosolic strands as usually seen with full-length STIM1 or cytosolic STIM1 fragments, probably by overcoming decreases of affinity with local tethering. Only the introduction of disturbing mutations in both NH₂ and COOH termini (W76C, K85E, L273S, L276D) results in loss of function of the CAD/SOAR-Orai linked constructs. These studies underline that Orai1 NH₂ and COOH termini contribute synergistically to the interaction with STIM1 for control of gating or ion selectivity. Palty and Isacoff (115) have suggested, alternative to a stepwise STIM1 coupling, which initially starts with STIM1 binding to the Orai1 COOH terminus and subsequently to the NH₂ terminus, that the NH₂- and COOH-terminal binding sites assemble to a distinct binding pocket for STIM1 that controls gating and selectivity of Orai channels.

The NMR structural resolution of a complex of a STIM1 COOH-terminal fragment and Orai1 COOH terminus complemented by mutagenesis studies has already characterized the binding pocket of STIM1 (SOAP) embedding the Orai1 COOH terminus (see Fig. 3C). It is of note that this complex represents only part of the interactions involved in physiological, full-length Orai1 activation, as particularly the Orai1 NH₂ terminus and the CC3_ext domain of STIM1 are missing. Here, complexes of larger STIM1 COOH-terminal portions together with additional Orai1 cytosolic strands or the full-length Orai1 may ultimately provide structural resolution closest to the physiological STIM-Orai1 interaction. Moreover, although coimmunoprecipitation studies have revealed no interaction with the third cytosolic Orai domain, i.e., the loop2 linking TM2 and TM3, its role in the cooperative coupling of STIM1 to Orai1 NH₂ and COOH termini still needs to be reevaluated.

Furthermore, a clear picture of the structural requirements as well as molecular determinants of STIM1 for its coupling to Orai1 is still missing, as, strikingly, the CAD/SOAR crystal structure and the STIM1 fragment NMR structure display quite distinct orientations (Fig. 1B, Fig. 3, A and B). A switch between these two structures would require substantial conformational changes, conceivable with a scissorlike opening at the pivot (around aaY361) and separation of the CC2 domains to form the SOAP. While the STIM1 fragment NMR structure (161) adopts a conformation that fits well with an interaction with the antiparallel-oriented COOH termini in the dOrai crystal structure, how the SOAR crystal structure in its present form would couple to Orai1 remains unknown.

Stoichiometry of STIM1/Orai1 Complex Required for Its Activation

The coupling of STIM1 to Orai1 upon store depletion results in the formation of an oligomeric, heteromeric complex, where the exact stoichiometry of interacting subunits still remains unclear. Several studies have reported that the activation of Orai1 depends on the number of interacting STIM1 proteins (59, 79, 145). Scrimgeour et al. (145, 146) have demonstrated that the extent of CRAC current inactivation depends on the number of STIM1 molecules that bind to the Orai1 channel. The fewer STIM1 proteins interact with Orai1, the fewer CRAC channel currents inactivate. Furthermore, an enhanced STIM1-to-Orai1 ratio increases selectivity for divalent cations as well as decreasing 2-aminoethoxydiphenyl borate (2-APB)-mediated current potentiation (145, 146).

Patch-clamp studies with cells containing varying STIM1-to-Orai1 concentration or fusion proteins of Orai1 (59) and tandem dimers of extended CAD have shown that eight STIM1 molecules (79) are needed for maximal CRAC current activation and inactivation. Nevertheless, only one or two STIM1 proteins are sufficient for coupling to Orai1 channels at the ER-PM junctions (59). Utilization of Orai1 and Orai1 V102A constructs tethered to single and tandem CAD/SOAR domains has revealed an enhancement of Ca²⁺ selectivity upon an increased amount of bound STIM1 fragments (101). Thus these studies suggest that activation of CRAC channels is not established in an “all-or-none” manner but evolves as a graded process involving up to eight STIM1 molecules (79). However, from the point of view of the crystallized hexameric Orai structure, how eight STIM1 molecules may couple to six Orai subunits is elusive. The recent structural NMR resolution of the SOAP structure has revealed a coupling of a STIM1 dimeric fragment to two Orai COOH termini, suggesting rather a STIM1-to-Orai1 ratio of 1:1 in an active complex (161). Thus six STIM1 molecules potentially attach to the six Orai proteins, or in other words one STIM1 dimer interacts with each of the three Orai dimers. Alternatively, to fulfil the requirements of a STIM1-to-Orai1 ratio of 2:1, 12 STIM1 proteins are needed to activate an Orai hexamer. A study by Zhou et al. (194) has hypothesized a completely new STIM1-Orai1 coupling model utilizing the F394H mutation (173) that disrupts STIM1 interaction with and activation of Orai1. SOAR-tandem constructs, containing either two wild-type SOARs or one wild-type together with one mutated F394H SOAR, activate Orai1 to comparable current levels and display similar interaction as determined by FRET. Only a SOAR tandem with both monomers carrying the F394H mutation results in loss of coupling to and activation of Orai1 channels. Furthermore, an expressed PM-fixed Orai1-COOH terminus construct yields half-reduced interaction with the SOAR tandem carrying one F394H mutation compared with the SOAR wild-type tandem. On the basis of these results, the authors suggest a unimolecular interaction between one Orai channel subunit and one STIM1 within the STIM1 dimer. Furthermore, they hypothesize that the other STIM1 within the STIM1 dimer probably couples to an Orai subunit of an adjacent Orai1 hexamer, thus providing the ability for Orai1 channels to arrange into clusters. It is of note that this interesting model is based on the assumption that STIM1 (or STIM1 F394H mutant) interaction with the PM-targeted Orai1 COOH terminus mimics those occurring in the full-length Orai1 channel complex, where the COOH termini within an Orai1 dimer are arranged in an antiparallel dimeric form, at least as found in the crystallized dOrai channel structure. Mechanistically, the proposed unimolecular manner of STIM1-Orai interactions leaves open the question of how one STIM1 fragment is able to induce alterations within an Orai1 COOH terminus dimer finally resulting in channel activation. Potentially, to fill both COOH-terminal STIM1 binding sites of one Orai dimer, two STIM1 monomers, each of another STIM1 dimer, might interact with the COOH termini to induce activation. Further evidence may be obtainable by construction of a STIM1 monomeric form provided that it can still attain a conformation for interaction with and activation of Orai1 channels. A clustering of Orai channels is, however, also conceivable via a bimolecular binding of a STIM1 dimer to an Orai1 dimer, as the STIM1 proteins possess the ability to form clusters in the activated state involving the CC3_ext domain (44). Hence, it is tempting to speculate that the CC3_ext domains may not only contribute to the formation of oligomeric STIM1 assemblies of the Orai1 channel complex they are interacting with (161) but additionally enable the linkage of adjacent Orai channels into larger clusters. However, further experimental evidence is required for whether and how STIM1 dimers may arrange Orai channels into clusters.

Gating of Orai Channels

Permeability of CRAC/Orai channels.

CRAC channels exhibit an exquisite Ca²⁺ selectivity with a 1,000 times higher permeation for Ca²⁺ than for Na⁺ (61). Thus Orai Ca²⁺ currents display strong inward rectification with a reversal potential higher than +60 mV (62, 86). CRAC channels have a very low single-channel conductance that has so far precluded direct recording of single-channel currents. Recently, however, optical recordings have been obtained with an approach in which a genetically encoded calcium indicator has been fused to Orai1 proteins (39). Multiple conductance states of the open channel together with periodic fluctuations in Orai1 activity have been observed in presence of CAD/SOAR (39). Orai channels also conduct small monovalent ions such as Na⁺, Li⁺, or K⁺, but only as long as the monovalent solution is free of divalent ions. The blockage of monovalent Orai currents occurs by addition of Ca²⁺ in the micromolar range (8, 61, 76, 130, 131, 164). A single Ca²⁺ ion is supposed to inhibit the large monovalent Orai currents, and Ca²⁺ block occurs in a voltage-dependent manner (130, 179). Similarly, L-type Ca_V channels also bind Ca²⁺ tightly to a high-affinity binding site to abolish Na⁺ entry (140). However, in contrast to L-type or TRPV6 channels, Cs⁺ is impermeant for Orai channels. The reason for that has been supposed to lie in a very narrow pore diameter of 3.8–3.9 Å, which is significantly smaller than that of Ca_V channels (130, 179). Interestingly, resolution of the dOrai crystal structure revealed a diameter of 6 Å at the narrowest region of the pore (Fig. 3B), which is obviously at variance with the diameter obtained experimentally by Yamashita et al. (179). Potentially the pore diameter is altered by the interaction of Orai with STIM1.

Ion conduction pathway of the Orai pore.

The ion conduction pathway of multimeric Orai channels is formed by TM1 together with the ETON region comprising residues 74–90 (see Fig. 2C). A first picture of the pore has been drawn based on coherent electrophysiological results, cysteine scanning mutagenesis studies, and determination of the block of Orai currents by either oxidative cross-linking of cysteines or cadmium (99, 179, 192). Finally, this perception of the Orai pore has been confirmed by the later published dOrai crystal structure (63), which revealed an association of six TM1 helices in the middle of the Orai complex constituting the conduction pathway. The Orai pore (see Fig. 2C) consists of an external vestibule, the selectivity filter, and a hydrophobic cavity, followed by a basic region (63). Briefly, the external vestibule includes negatively charged residues that attract Ca²⁺ ions (51). The selectivity filter is exclusively formed by E106 at the more extracellular side of TM1, which is followed by V102, F99, and L95 constituting the hydrophobic cavity. Finally, at the more cytosolic side the pore ends with a basic region including R91, K87, and R83 (32, 63, 138).

The external vestibule (see Fig. 2C) is formed by the TM1-TM2 loops, each of which includes three negatively charged residues (D110, D112, D114). Their triple mutation to alanines alters ion selectivity and induces a widening of the pore (179), while single cysteine or alanine substitutions leave the Orai1 mutants' Ca²⁺ selectivity unaltered (51, 99). These loop segments have been shown via the substituted cysteine accessibility method (SCAM) to tightly couple with large (>8 Å) as well as small (<3 Å) positively as well as negatively charged MTS reagents (99). These results suggest that the first loops surround a large vestibule that is able to accommodate bulky compounds of different size and charge. Furthermore, disulfide cross-linking studies as well as Cd⁺ block experiments have suggested that these loop regions are very flexible (102). Recent data by Frischauf et al. (51) have revealed that these negatively charged residues (D110, D112, D114) function as a Ca²⁺ accumulating region (CAR) of Orai channels (Fig. 4), probably decreasing the energetic barrier for Ca²⁺ ions to enter the pore. In particular, D110 and D112 have been demonstrated by MD simulations to function as transient Ca²⁺ binding sites before Ca²⁺ ions reach the selectivity filter located 1.2 nm away from CAR. A substitution of D110 to an alanine results in reduced permeation of Ca²⁺, particularly at lower extracellular Ca²⁺ concentrations, likely because of a shift of Ca²⁺ binding to D112 and D114 and thus an enhanced energy barrier between CAR and the selectivity filter. Besides the interaction of the TM1-TM2 loop1 with Ca²⁺, additional electrostatic interactions have been discovered between TM1-TM2 loop1 and the TM3-TM4 connecting loop3, enabling fine-tuning of Ca²⁺ accumulation to the pore. Cysteine-induced cross-linking of D112 and R210 results in reduced store-operated current densities, which were enhanced by 400% upon breakage of disulfide bonds. Hence, the loop3 apparently competes with Ca²⁺ binding to loop1, thereby finely adjusting the Ca²⁺ permeation (51).

Fig. 4. — Hypothetical model for gating of Orai1 channels: cartoon representation of the closed (A) and open (B) states of Orai1 when coupled to STIM1-CAD/SOAR or STIM1-CC1_α3-CC2. A: in the closed conformation of the Orai1 channel, TM1 is locked in a place that prevents ion permeation. The conformation of TM1 is adjusted by TM2, TM3, and TM4, potentially by the highlighted residues, which can induce constitutive activity upon their mutation. STIM1 assumes the tight, inactive state. B: coupling of Orai1 to STIM1 (here the 2 structurally resolved STIM1 fragments are displayed) induces the open state of Orai1. Both Orai1 NH₂-terminal and COOH-terminal interactions with STIM1 are required, to alter the angle at P245 in TM4 and induce TM1 reorientations that switch the hydrophobic gate(s) and render the Orai1 pore conducting. Further alterations in the orientation of the other TM regions are likely to contribute. Focus in this panel is not laid on stoichiometry and how STIM1 couples, but conformational changes occurring upon Orai1 gating are emphasized.

Interestingly, at analogous sites where Orai1 contains the three glutamines, Orai2 and Orai3 contain a mixture of glutamates, glutamines, and aspartates. While homomeric Orai channels exhibit inward-rectifying, Ca²⁺-selective currents, heteromeric assemblies of Orai isoforms, which display an asymmetric composition of the glutamates and aspartates, are less Ca²⁺ selective with increased Cs⁺ permeation (142). These results further support the concept that this acidic Ca²⁺ coordination site in the first loop besides Ca²⁺ permeation also regulates Ca²⁺ selectivity of Orai channels.

Upon the attraction of Ca²⁺ ions via those negatively charged residues in the loop1 region they are further guided to the selectivity filter, solely formed by E106 located at the extracellular end of TM1 (128, 169, 181). Based on the hexameric crystal structure (see Fig. 3, B and C), the selectivity filter is composed of six glutamate residues (63). Electrophysiological studies have reported that Orai1 E106A/Q lost function, while E106D reduced the Ca²⁺ selectivity and widened the pore diameter to ∼5.4 Å (179). This enhanced pore size is accompanied by a further relieved steric hindrance for Cs⁺, thus leading to diminished Ca²⁺ selectivity (179). Cysteine cross-linking has revealed close proximity of E106 residues and higher rigidity of TM1 helix residues aa99–104 along the Orai pore (192). Thus close positioning of E106 residues in the hexameric pore as well as rigidity of the adjacent helical stretch have been supposed to coordinate Ca²⁺ at E106 (192). In line with, recent MD simulations have revealed under equilibrium conditions one Ca²⁺ ion bound to E106 (51). This ring of negatively charged residues provides a negative electrostatic potential forming the selectivity filter and potentially functions as a gate for Ca²⁺ ions to enter the channel (101).

Deeper in the Orai1 pore, the selectivity filter is followed by the wide, hydrophobic cavity including V102, F99, and L95 (see Fig. 2C). These residues, except F99, point directly into the pore, which is in line with their ability to dimerize upon cysteine substitutions and suggests that they provide extensive van der Waals forces to each other (192). Moreover Cd⁺ blockage studies reveal effective inhibition of V102C, G98C, and L95C mutants (102). Since Orai1 V102C becomes constitutively active in the absence of STIM1, somehow locking Orai1 into an open conformation, V102 has been suggested to form the hydrophobic gate (Fig. 4) (101). In line with this, MD simulations for dOrai channel have revealed that a V174A mutation (corresponding to V102A in human Orai1) provides a more favorable permeation pathway than the wild-type channel based on potentials of mean force for the translocation of a single Na⁺ ion (37). However, the simulations have been performed in the presence of Na⁺ but not Ca²⁺.

V102 has been further established as the hydrophobic gate because STIM1 coupling to Orai1 induces conformational changes close to E106 and V102 that have been observed via alterations in the luminescence of Tb³⁺ bound in the pore (54). Hence, Orai gating and ion selectivity are closely coupled, since upon channel activation V102 and E106 together undergo a conformational change and are located only one helix turn apart from each other (54, 101).

Additionally, the hydrophobic cavity includes G98 (see Fig. 2, C and D), suggested to function as a flexible gating hinge (184), common for diverse other ion channels (122, 175, 188). It is assumed that G98 provides flexibility to the upstream pore-lining region, enabling Ca²⁺ ions to easily pass the pore after the selectivity filter. The Orai1 G98D mutant exhibits nonselective, constitutively active currents. As the additional introduction of the permeation-blocking R91W mutation is ineffective in inhibiting the activity of Orai1 G98D in contrast to Orai1 V102A/C channels, one may assume a larger and/or less flexible widening of the pore with the former G98D mutation.

The hydrophobic portion of the pore is followed by a basic region extending into the cytosol, forming the elongated pore of Orai1. This extended region, the so-called ETON region (35), likely provides an electrostatic barrier via the three positively charged amino acids R91, K87, and R83 (see Fig. 2C). Based on the crystal structure, all three residues point into the pore, which is in line with R91C exhibiting cysteine cross-linking (102, 192). In the closed-channel state, these residues are assumed to block Ca²⁺ entry probably either due to bound anions or simply by electrostatic repulsion in this region (63). Single-point mutation of R91 to a hydrophobic residue that is associated with SCID assumedly generates a robust hydrophobic barrier (63) that hinders Ca²⁺ flow through the elongated pore. The ETON region not only functions as a potential gate but also contributes a binding interface for STIM1 (35).

In aggregate, permeation through Orai channels is initiated via the attraction of Ca²⁺ ions by the Ca²⁺ accumulating region in loop1, and then Ca²⁺ ions are guided to the selectivity filter constituted by the single glutamate E106 of each Orai1 subunit. Afterwards, Ca²⁺ ions pass the hydrophobic regions and are finally released into the cytosol, potentially via the repulsion of positive-charged residues at the end of the pore.

TM Regions Surrounding TM1 Further Contribute to Orai Gating

Gating of Orai channels into the open state occurs via STIM1 binding to both Orai1 COOH and NH₂ termini (Fig. 4), thereby inducing a conformational change within the Orai hexamer. The TM1 helices lining the permeation pathway for Ca²⁺ in Orai channels are probably opened via a change in the orientation of pore-lining residues of TM1, allowing Ca²⁺ to pass the pore. Which structural change actually occurs in the Orai1 channel complex and particularly within the TM1 helices remains unknown so far.

Mutagenesis studies have revealed specific residues that are required to keep Orai channels in the closed state. As mentioned above, Orai1 V102A/C and Orai1 G98D yield nonselective, constitutively active currents. These results suggest that V102 and G98 (see Fig. 2D, Fig. 4A) are involved in keeping Orai1 channels in the closed state (101, 184).

Besides residues in TM1, it is known that several residues in TM2, TM3, as well as TM4 also affect gating or contribute to the control of the closed state of the pore even if they do not line the pore, as their mutation leads to altered gating properties or even constitutively active channels.

In TM2, L138 has been suggested to keep Orai1 channels in the closed state, as its mutation to a phenylalanine (L138F) leads to constitutively active currents (40). This residue is located at the TM1-TM2 interface (Fig. 2D, Fig. 4A). The L138F mutation has been found to cause tubular aggregate myopathy (40).

In TM3, mutation of several residues has been shown to modulate selectivity and gating of Orai1 channels (Fig. 2D, Fig. 4A). Mutation of the tryptophan to a cysteine W176C induces constitutive, but less Ca²⁺-selective, currents (157). The glycine G183 in TM3 is required for unconfined gating of Orai1 channels, as its substitution to an alanine fully abolishes store-operated activation but leads to altered sensitivity to 2-APB (157). The analog Orai3 G158C exhibits altered kinetics in response to 2-APB and an impaired closing of the channel upon 2-APB washout (4). These effects of G158C have been attributed to a potential TM2-TM3 interaction with an endogenous cysteine, C101, which probably controls the activation state of Orai1 channels (4).

Additionally, the conserved glutamate E190 in TM3 (Fig. 2D, Fig. 4A) is involved in the maintenance of Orai's Ca²⁺ selectivity. Its substitution to an alanine or glutamine results in increased permeation of Cs⁺, a pore diameter increased to 7 Å, and decreased 2-APB activation (179). It has been supposed that E190 allosterically affects the pore, probably via alterations of intramolecular TM interactions.

Furthermore, P245 located at the kink of TM4 (Fig. 2D, Fig. 4A) is involved in controlling the closed state of Orai1 channels. The Stormorken disease-related mutation P245L (114) has been shown to cause constitutive activation, although the residue is located far away from the pore. Interestingly, substitution of this proline by all the other amino acids leads to constitutive activation, suggesting that only the proline keeps Orai1 channels in the closed state (115).

In summary, not only residues in TM1 but also several others in the surrounding pore TM regions are involved in keeping Orai1 channels in the closed state. Strikingly, G98, G183, and P245 are all situated in the same membrane plane (117). Hence, it seems that even if these residues are not lining the pore they somehow contribute indirectly to gating and/or permeation of Orai channels. Constitutively active mutants probably mimic, at least partially, one step of the conformational change occurring upon STIM1 binding. It may be hypothesized that the simultaneous binding of STIM1 to both the NH₂ and COOH termini of Orai1 initiates a synchronized rearrangement of TM helices leading to the open state (Fig. 4B). Here STIM1 binding to Orai1 may alter the orientation of the NH₂ and COOH termini, which presumably affects TM helix arrangements, partially destabilizes the packed closed conformation, and gates the channel finally via TM1 reorientation into the open state (Fig. 4B).

STIM1 Tunes Orai Channel Gating Characteristics

Interestingly, STIM1 is not only responsible for CRAC channel gating but also tunes the hallmarks of CRAC channels, i.e., high Ca²⁺ selectivity and fast Ca²⁺-dependent inactivation. Functional coupling of STIM1 to Orai1 induces gating but also regulates selectivity. This has been initially revealed by the Orai1 V102A/C mutants. Its constitutive, nonselective currents regain Ca²⁺ selectivity in the presence of STIM1. Thus STIM1 is able to fine-tune the ion selectivity of the constitutively open Orai1 V102A/C channels. High Ca²⁺ selectivity is only established as long as STIM1 binding is intact to both the NH₂ as well as COOH terminus of Orai1 V102A/C (35, 100, 101). In contrast to Orai1 V102A, Orai1 G98D cannot regain Ca²⁺ selectivity in the presence of STIM1 (184). In the absence of STIM1, Orai1 V102A/C displays poor Ca²⁺ selectivity and enables permeation of Na⁺, Cs⁺, and several other large cations, which are not permeant through wild-type Orai1/CRAC channels (101). The coupling of Orai1 V102A/C to STIM1 enhances Ca²⁺ selectivity together with a narrowing of the pore, thus restoring dimensions of the wild-type Orai1 channel.

Similarly, constitutively active Orai1 P245L currents display reduced selectivity compared with that obtained by store depletion in the presence of STIM1. Furthermore, Orai1 P245L exhibits fast Ca²⁺-dependent inactivation (CDI) in the presence of STIM1 but not, however, in its absence (117). Hence, it seems that despite the fact that the P245L mutation induces a constitutively active Orai1 state, STIM1 is indispensable to fully attain the selectivity as well as fast CDI of wild-type STIM1-activated Orai1 currents.

It is not unique to the V102A/C and P245L mutant channels that STIM1 tunes their ion selectivity. Wild-type Orai1 currents have also been shown to display increasing ion selectivity with progressive amounts of bound STIM1 (101). Hence, both mutants potentially exhibit an intermediate active state, which reaches all of the CRAC channel characteristics only in the presence of STIM1. How STIM1 binding causes the changes in ion selectivity or inactivation remains to be elucidated at a structural level. Nevertheless, one might hypothesize that STIM1 binding to the NH₂ terminus connected to TM1 influences the conformations of the selectivity filter. Further STIM1 coupling to the Orai COOH terminus is likely linked to structural alterations in the TM4 domains, which propagate further via TM3 and TM2 to TM1 regions (Fig. 4B).

Inactivation of Orai Channels

Orai/CRAC channel activity is inhibited via so-called Ca²⁺ dependent inactivation (CDI), which represents an important feedback mechanism to control intracellular Ca²⁺ concentrations. Ca²⁺-dependent inactivation of Orai channels is separated in fast (FCDI) and slow (SCDI) CDI (23). FCDI has been reported to occur within milliseconds after channel activation (120, 129) and is typically observed during a hyperpolarizing voltage step as a decrease in CRAC currents over tens of milliseconds (61, 197). In contrast, SCDI takes several minutes for completion (120, 129).

CDI is controlled by several components in the CRAC channel signaling cascade: STIM1 and Orai as well as additional regulatory proteins, calmodulin (CaM) and SARAF. Several cytosolic regions of the STIM1 COOH terminus and Orai have been identified to determine Orai channel inactivation.

STIM1 has been suggested to define the extent of inactivation in dependence of the STIM1-to-Orai1 ratio (145, 146). Furthermore, an acidic cluster (aa475–483) termed the CRAC modulatory domain (CMD) in STIM1 COOH terminus is indispensable for FCDI of Orai/CRAC channels (33, 75, 112). Alanine substitutions of these negatively charged amino acids in the CMD reduce inactivation of all Orai1-3 channels as well as native CRAC currents in rat basophilic leukemia (RBL) cells (33, 75). Moreover, it has been shown for Orai1 V102A as well as Orai1 P245L that, despite their constitutive activity, STIM1 is required to induce inactivation characteristics typical for STIM1-mediated Orai1 currents.

FCDI and SCDI of STIM1-Orai1-mediated currents have been recently reported to be controlled by an additional ER-resident protein, SARAF (23, 67, 116). While the mechanism for FCDI regulation via this auxiliary protein is unclear, the role of SARAF in SCDI has been uncovered (23, 67, 94). SARAF interacts with the CAD/SOAR domain of STIM1, however, only in the presence of Orai1 (67). SARAF is regulated by a STIM1 domain downstream of SOAR, the so-called COOH-terminal inhibitory domain (CTID), which underlies a complex mechanism of interaction of SARAF with different portions of CTID (67). In the presence of SARAF, STIM1-Orai1-mediated currents display SCDI, which is reduced when the polybasic cluster is lacking, PIP₂ is depleted, or STIM1 proteins are targeted to PIP₂-poor regions (94). The coregulation of STIM1 and SARAF is further supported by septin 4 and ESyt1, which contribute to keep STIM1/Orai1 complexes in PIP₂-rich regions (23, 94).

All three Orai channels exhibit FCDI within the first 100 ms of a voltage step; however, it is three times stronger for Orai3 compared with Orai1 or Orai2 (75, 86, 142). While Orai1 currents display a late reactivation phase, Orai2 and Orai3 channels further exhibit a slow inactivation phase over a 2-s voltage step (86, 142). In contrast to overexpressed Orai proteins, the inactivation of native CRAC currents in RBL mast cells (33, 197) is much more distinctive and lacks the characteristic reactivation phase seen with Orai1, suggesting that further players account for the inactivation of native CRAC channels.

Located within the Orai1 NH₂ terminus, the specific proline/arginine-rich region has been shown to mediate reactivation (49). Moreover, FCDI has been shown to be regulated by CaM binding to the Orai NH₂ terminus. Studies with isolated Orai1 and Orai3 NH₂-terminal fragments have revealed binding to CaM. In accordance, mutations within Orai1 NH₂ terminus (A73E; W76E/A/S, Y80E) disrupting as well as deletions in the Orai3 NT removing the CaM binding site result in loss of FCDI (10, 49, 112). In line with this, with Orai1 NH₂ terminus mutagenesis studies (112) a crystal structure of Orai1 NH₂ terminus and CaM in complex has confirmed an interaction of CaM with Orai1 W76 and Y80 (89). Nevertheless, overexpression of CaM-EF-hand mutants together with STIM1 and Orai1 does not result in reduced inactivation (88), suggesting that CaM is not prebound but rather associates with the Orai1 channels after increases in cytosolic Ca²⁺ concentrations. Furthermore, as W76 and Y80 are facing the interior of the pore in the dOrai1 crystal structure, it remains unclear how CaM fits into this area without strong conformational changes into the open state (132).

As demonstrated by chimeric and mutational approaches, the intracellular loop of Orai1 connecting TM2 and TM3 modulates fast and slow inactivation upon a hyperpolarizing voltage pulse (49, 156). Substitution of the amino acid stretch 151-VSNV-154 by four alanines impairs fast inactivation. Furthermore, overexpression or intracellular perfusion of a short peptide encompassing this region reduces CRAC currents. Hence, loop2 might either function as blocking particle or act in an allosteric manner on inactivation.

Orai COOH terminus exhibits a complex role in the modulation of fast inactivation. Fast inactivation is diminished for Orai2 and Orai3 chimeras with the COOH terminus substituted by that of Orai1 (75), which has been attributed to three glutamates only present in Orai2 and Orai3 COOH termini (75). In contrast, the swap of Orai1/3 COOH termini leaves fast inactivation unaffected. It is of note that the cytosolic NH₂ and COOH termini and loop2 affect Orai inactivation/gating in a cooperative manner (49). Additionally, fast inactivation is determined by negatively charged residues within the outer pore vestibule of Orai1 channels (179). Hence, Orai channels employ diverse regions to control CDI. The interpretation of potential inactivation sites may require a strict control of STIM/Orai stoichiometry (59, 145).

In summary, FCDI of Orai channels is regulated via negatively charged residues in both STIM1 and Orai. Moreover, the second intracellular loop as well as CaM acting on Orai NH₂ terminus affects fast inactivation. SCDI of Orai currents is regulated via STIM1 and SARAF; however, whether SCDI also involves Orai domains remains so far unclear.

Perspectives

Within the past 10 years substantial advances have already been made toward the identification of the molecular components of the CRAC channel family together with access to their three-dimensional atomic structures. Nevertheless, several questions are still unresolved.

Regarding STIM1, only a portion of its cytosolic COOH terminus has been characterized at atomic resolution, where currently the whole and a part of the CAD/SOAR domain are available, showing significant differences in their structure. Here, further structural studies are required, particularly with longer STIM1 COOH-terminal fragments for clarification of the intra- and intermolecular interactions that contribute to the regulation, switching STIM1 from its tight, inactive to its extended, active conformation. Locking the extended conformation by L251S or L258G mutation may help to obtain structures that mimic the active state of cytosolic STIM1. Moreover, the crystal structure of Orai1 displays the closed state, while the structure of the open state is still unresolved. Here, constitutively, active Orai channels (e.g., Orai1 P245X) that are locked in an open state may help to address open channel conformation(s) by X-ray crystallography. The detailed molecular mechanism for how Orai channels are gated via STIM1 into the open state is only partially understood. So far, the NMR structure from a complex of a STIM1 fragment and the Orai1 COOH terminus has led to the characterization of the association pocket (SOAP), yet that with the Orai1 NH₂ terminus is still missing. Moreover, the interaction of STIM1 with the full-length Orai1 channel will require structure-resolving studies of these proteins in complex. These studies may reveal the conformational changes that take place upon Orai channel activation including rearrangements of the cytosolic strands linked with those among the TM regions. Single-particle cryo-EM (7, 25) may provide an additional, valuable approach here, as it has been quite successfully used with ion channels such TRPV1 (81) or the IP₃ receptor (45), obtaining almost similar resolutions as with crystallography.

The current achievements in understanding of the communication between STIM and Orai proteins will further enable us to widen our knowledge on physiological downstream signaling of the CRAC channels (70, 118). Sophisticated control of this communication by light (55, 65) has recently opened the Ca²⁺ signaling field to optogenetics. Potential proteins modulating the STIM/Orai communication, such as CRACR2A (155), SARAF (23, 116), Septin (147), or STIMATE (69), add further complexity to the native CRAC channel system and have the potential for a fine-tuned interference with drugs. Although several CRAC channel inhibitors are already available (66, 119, 133), their precise site of action has so far remained unclear. Besides the classical pore blockers, the complex machinery behind the CRAC current assumedly offers numerous interventions to interfere with protein-protein interactions in the CRAC channel complex to discover novel CRAC channel modulators with significant therapeutic potential in immune deficiency, autoimmune, or allergic disorders.

GRANTS

This work was supported by the Austrian Science Fund (FWF projects P25210 and P27641 to I. Derler and FWF projects P25172 and P27263 to C. Romanin). I. Jardin was supported by MINECO (Grant BFU2013-45564-C2-1-P) and Junta de Extremadura-FEDER (GR15029).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author(s).

AUTHOR CONTRIBUTIONS

Author contributions: I.D. and I.J. prepared figures; I.D. and C.R. drafted manuscript; I.D., I.J., and C.R. approved final version of manuscript.

ACKNOWLEDGMENTS

We thank R. Schindl for carefully reading the manuscript.

REFERENCES

1.Altin JG, Bygrave FL. Second messengers and the regulation of Ca²⁺ fluxes by Ca²⁺-mobilizing agonists in rat liver. Biol Rev Camb Philos Soc 63: 551–611, 1988. [DOI] [PubMed] [Google Scholar]
2.Ambily A, Kaiser WJ, Pierro C, Chamberlain EV, Li Z, Jones CI, Kassouf N, Gibbins JM, Authi KS. The role of plasma membrane STIM1 and Ca²⁺ entry in platelet aggregation. STIM1 binds to novel proteins in human platelets. Cell Signal 26: 502–511, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.Ambudkar IS. TRPC1: a core component of store-operated calcium channels. Biochem Soc Trans 35: 96–100, 2007. [DOI] [PubMed] [Google Scholar]
4.Amcheslavsky A, Safrina O, Cahalan MD. Orai3 TM3 point mutation G158C alters kinetics of 2-APB-induced gating by disulfide bridge formation with TM2 C101. J Gen Physiol 142: 405–412, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Amcheslavsky A, Wood ML, Yeromin AV, Parker I, Freites JA, Tobias DJ, Cahalan MD. Molecular biophysics of Orai store-operated Ca²⁺ channels. Biophys J 108: 237–246, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Baba Y, Hayashi K, Fujii Y, Mizushima A, Watarai H, Wakamori M, Numaga T, Mori Y, Iino M, Hikida M, Kurosaki T. Coupling of STIM1 to store-operated Ca²⁺ entry through its constitutive and inducible movement in the endoplasmic reticulum. Proc Natl Acad Sci USA 103: 16704–16709, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Bai XC, McMullan G, Scheres SH. How cryo-EM is revolutionizing structural biology. Trends Biochem Sci 40: 49–57, 2015. [DOI] [PubMed] [Google Scholar]
8.Bakowski D, Parekh AB. Permeation through store-operated CRAC channels in divalent-free solution: potential problems and implications for putative CRAC channel genes. Cell Calcium 32: 379–391, 2002. [DOI] [PubMed] [Google Scholar]
9.Barr VA, Bernot KM, Srikanth S, Gwack Y, Balagopalan L, Regan CK, Helman DJ, Sommers CL, Oh-Hora M, Rao A, Samelson LE. Dynamic movement of the calcium sensor STIM1 and the calcium channel Orai1 in activated T-cells: puncta and distal caps. Mol Biol Cell 19: 2802–2817, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Bergsmann J, Derler I, Muik M, Frischauf I, Fahrner M, Pollheimer P, Schwarzinger C, Gruber HJ, Groschner K, Romanin C. Molecular determinants within N terminus of Orai3 protein that control channel activation and gating. J Biol Chem 286: 31565–31575, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Berna-Erro A, Redondo PC, Rosado JA. Store-operated Ca²⁺ entry. Adv Exp Med Biol 740: 349–382, 2012. [DOI] [PubMed] [Google Scholar]
12.Berna-Erro A, Woodard GE, Rosado JA. Orais and STIMs: physiological mechanisms and disease. J Cell Mol Med 16: 407–424, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
13.Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4: 517–529, 2003. [DOI] [PubMed] [Google Scholar]
14.Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1: 11–21, 2000. [DOI] [PubMed] [Google Scholar]
15.Bogeski I, Al-Ansary D, Qu B, Niemeyer BA, Hoth M, Peinelt C. Pharmacology of ORAI channels as a tool to understand their physiological functions. Expert Rev Clin Pharmacol 3: 291–303, 2010. [DOI] [PubMed] [Google Scholar]
16.Bogeski I, Kilch T, Niemeyer BA. ROS and SOCE: recent advances and controversies in the regulation of STIM and Orai. J Physiol 590: 4193–4200, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Brandman O, Liou J, Park WS, Meyer T. STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca²⁺ levels. Cell 131: 1327–1339, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Cahalan MD. STIMulating store-operated Ca²⁺ entry. Nat Cell Biol 11: 669–677, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Cahalan MD, Chandy KG. The functional network of ion channels in T lymphocytes. Immunol Rev 231: 59–87, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Cai X. Molecular evolution and functional divergence of the Ca²⁺ sensor protein in store-operated Ca²⁺ entry: stromal interaction molecule. PLoS One 2: e609, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Calloway N, Holowka D, Baird B. A basic sequence in STIM1 promotes Ca²⁺ influx by interacting with the C-terminal acidic coiled coil of Orai1. Biochemistry 49: 1067–1071, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Calloway N, Vig M, Kinet JP, Holowka D, Baird B. Molecular clustering of STIM1 with Orai1/CRACM1 at the plasma membrane depends dynamically on depletion of Ca²⁺ stores and on electrostatic interactions. Mol Biol Cell 20: 389–399, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Cao X, Choi S, Maleth JJ, Park S, Ahuja M, Muallem S. The ER/PM microdomain, PI(4,5)P₂ and the regulation of STIM1-Orai1 channel function. Cell Calcium 58: 342–348, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Chang CL, Hsieh TS, Yang TT, Rothberg KG, Azizoglu DB, Volk E, Liao JC, Liou J. Feedback regulation of receptor-induced Ca²⁺ signaling mediated by E-Syt1 and Nir2 at endoplasmic reticulum-plasma membrane junctions. Cell Rep 5: 813–825, 2013. [DOI] [PubMed] [Google Scholar]
25.Cheng Y. Single-particle cryo-EM at crystallographic resolution. Cell 161: 450–457, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Chvanov M, Walsh CM, Haynes LP, Voronina SG, Lur G, Gerasimenko OV, Barraclough R, Rudland PS, Petersen OH, Burgoyne RD, Tepikin AV. ATP depletion induces translocation of STIM1 to puncta and formation of STIM1-ORAI1 clusters: translocation and re-translocation of STIM1 does not require ATP. Pflügers Arch 457: 505–517, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Collins SR, Meyer T. Evolutionary origins of STIM1 and STIM2 within ancient Ca²⁺ signaling systems. Trends Cell Biol 21: 202–211, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Covington ED, Wu MM, Lewis RS. Essential role for the CRAC activation domain in store-dependent oligomerization of STIM1. Mol Biol Cell 21: 1897–1907, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Cui B, Yang X, Li S, Lin Z, Wang Z, Dong C, Shen Y. The inhibitory helix controls the intramolecular conformational switching of the C-terminus of STIM1. PLoS One 8: e74735, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
30.Darbellay B, Arnaudeau S, Bader CR, Konig S, Bernheim L. STIM1L is a new actin-binding splice variant involved in fast repetitive Ca²⁺ release. J Cell Biol 194: 335–346, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Demuro A, Penna A, Safrina O, Yeromin AV, Amcheslavsky A, Cahalan MD, Parker I. Subunit stoichiometry of human Orai1 and Orai3 channels in closed and open states. Proc Natl Acad Sci USA 108: 17832–17837, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Derler I, Fahrner M, Carugo O, Muik M, Bergsmann J, Schindl R, Frischauf I, Eshaghi S, Romanin C. Increased hydrophobicity at the N terminus/membrane interface impairs gating of the severe combined immunodeficiency-related ORAI1 mutant. J Biol Chem 284: 15903–15915, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Derler I, Fahrner M, Muik M, Lackner B, Schindl R, Groschner K, Romanin CA. Ca²⁺ release-activated Ca²⁺ (CRAC) modulatory domain (CMD) within STIM1 mediates fast Ca²⁺-dependent inactivation of ORAI1 channels. J Biol Chem 284: 24933–24938, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Derler I, Madl J, Schutz G, Romanin C. Structure, regulation and biophysics of I_CRAC, STIM/Orai1. Adv Exp Med Biol 740: 383–410, 2012. [DOI] [PubMed] [Google Scholar]
35.Derler I, Plenk P, Fahrner M, Muik M, Jardin I, Schindl R, Gruber HJ, Groschner K, Romanin C. The extended transmembrane Orai1 N-terminal (ETON) region combines binding interface and gate for Orai1 activation by STIM1. J Biol Chem 288: 29025–29034, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Derler I, Schindl R, Fritsch R, Romanin C. Gating and permeation of Orai channels. Front Biosci (Landmark Ed) 17: 1304–1322, 2012. [DOI] [PubMed] [Google Scholar]
37.Dong H, Fiorin G, Carnevale V, Treptow W, Klein ML. Pore waters regulate ion permeation in a calcium release-activated calcium channel. Proc Natl Acad Sci USA 110: 17332–17337, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Dong H, Sharma M, Zhou HX, Cross TA. Glycines: role in alpha-helical membrane protein structures and a potential indicator of native conformation. Biochemistry 51: 4779–4789, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Dynes JL, Amcheslavsky A, Cahalan MD. Genetically targeted single-channel optical recording reveals multiple Orai1 gating states and oscillations in calcium influx. Proc Natl Acad Sci USA 113: 440–445, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Endo Y, Noguchi S, Hara Y, Hayashi YK, Motomura K, Miyatake S, Murakami N, Tanaka S, Yamashita S, Kizu R, Bamba M, Goto Y, Matsumoto N, Nonaka I, Nishino I. Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca²⁺ channels. Hum Mol Genet 24: 637–648, 2015. [DOI] [PubMed] [Google Scholar]
41.Ercan E, Momburg F, Engel U, Temmerman K, Nickel W, Seedorf M. A conserved, lipid-mediated sorting mechanism of yeast Ist2 and mammalian STIM proteins to the peripheral ER. Traffic 10: 1802–1818, 2009. [DOI] [PubMed] [Google Scholar]
42.Fahrner M, Derler I, Jardin I, Romanin C. The STIM1/Orai signaling machinery. Channels (Austin) 7: 330–343, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Fahrner M, Muik M, Derler I, Schindl R, Fritsch R, Frischauf I, Romanin C. Mechanistic view on domains mediating STIM1-Orai coupling. Immunol Rev 231: 99–112, 2009. [DOI] [PubMed] [Google Scholar]
44.Fahrner M, Muik M, Schindl R, Butorac C, Stathopulos P, Zheng L, Jardin I, Ikura M, Romanin C. A coiled-coil clamp controls both conformation and clustering of stromal interaction molecule 1 (STIM1). J Biol Chem 289: 33231–33244, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Fan G, Baker ML, Wang Z, Baker MR, Sinyagovskiy PA, Chiu W, Ludtke SJ, Serysheva II. Gating machinery of InsP₃R channels revealed by electron cryomicroscopy. Nature 527: 336–341, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
46.Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441: 179–185, 2006. [DOI] [PubMed] [Google Scholar]
47.Feske S, Skolnik EY, Prakriya M. Ion channels and transporters in lymphocyte function and immunity. Nat Rev Immunol 12: 532–547, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Frischauf I, Muik M, Derler I, Bergsmann J, Fahrner M, Schindl R, Groschner K, Romanin C. Molecular determinants of the coupling between STIM1 and Orai channels: differential activation of Orai1-3 channels by a STIM1 coiled-coil mutant. J Biol Chem 284: 21696–21706, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
49.Frischauf I, Schindl R, Bergsmann J, Derler I, Fahrner M, Muik M, Fritsch R, Lackner B, Groschner K, Romanin C. Cooperativeness of Orai cytosolic domains tunes subtype-specific gating. J Biol Chem 286: 8577–8584, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
50.Frischauf I, Schindl R, Derler I, Bergsmann J, Fahrner M, Romanin C. The STIM/Orai coupling machinery. Channels (Austin) 2: 261–268, 2008. [DOI] [PubMed] [Google Scholar]
51.Frischauf I, Zayats V, Deix M, Hochreiter A, Jardin I, Muik M, Lackner B, Svobodova B, Pammer T, Litvinukova M, Sridhar AA, Derler I, Bogeski I, Romanin C, Ettrich RH, Schindl R. A calcium-accumulating region, CAR, in the channel Orai1 enhances Ca²⁺ permeation and SOCE-induced gene transcription. Sci Signal 8: ra131, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
52.Giordano F, Saheki Y, Idevall-Hagren O, Colombo SF, Pirruccello M, Milosevic I, Gracheva EO, Bagriantsev SN, Borgese N, De Camilli P. PI(4,5)P₂-dependent and Ca²⁺-regulated ER-PM interactions mediated by the extended synaptotagmins. Cell 153: 1494–1509, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
53.Grigoriev I, Gouveia SM, van der Vaart B, Demmers J, Smyth JT, Honnappa S, Splinter D, Steinmetz MO, Putney JW Jr, Hoogenraad CC, Akhmanova A. STIM1 is a MT-plus-end-tracking protein involved in remodeling of the ER. Curr Biol 18: 177–182, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
54.Gudlur A, Quintana A, Zhou Y, Hirve N, Mahapatra S, Hogan PG. STIM1 triggers a gating rearrangement at the extracellular mouth of the ORAI1 channel. Nat Commun 5: 5164, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
55.He L, Zhang Y, Ma G, Tan P, Li Z, Zang S, Wu X, Jing J, Fang S, Zhou L, Wang Y, Huang Y, Hogan PG, Han G, Zhou Y. Near-infrared photoactivatable control of Ca²⁺ signaling and optogenetic immunomodulation. eLife 4: 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
56.Hewavitharana T, Deng X, Soboloff J, Gill DL. Role of STIM and Orai proteins in the store-operated calcium signaling pathway. Cell Calcium 42: 173–182, 2007. [DOI] [PubMed] [Google Scholar]
57.Hogan PG, Lewis RS, Rao A. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu Rev Immunol 28: 491–533, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
58.Hogan PG, Rao A. Store-operated calcium entry: mechanisms and modulation. Biochem Biophys Res Commun 460: 40–49, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
59.Hoover PJ, Lewis RS. Stoichiometric requirements for trapping and gating of Ca²⁺ release-activated Ca²⁺ (CRAC) channels by stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci USA 108: 13299–13304, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
60.Hoth M, Niemeyer BA. The neglected CRAC proteins: Orai2, Orai3, and STIM2. Curr Top Membr 71: 237–271, 2013. [DOI] [PubMed] [Google Scholar]
61.Hoth M, Penner R. Calcium release-activated calcium current in rat mast cells. J Physiol 465: 359–386, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
62.Hoth M, Penner R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355: 353–356, 1992. [DOI] [PubMed] [Google Scholar]
63.Hou X, Pedi L, Diver MM, Long SB. Crystal structure of the calcium release-activated calcium channel Orai. Science 338: 1308–1313, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
64.Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF. STIM1 carboxyl-terminus activates native SOC, I_crac and TRPC1 channels. Nat Cell Biol 8: 1003–1010, 2006. [DOI] [PubMed] [Google Scholar]
65.Ishii T, Sato K, Kakumoto T, Miura S, Touhara K, Takeuchi S, Nakata T. Light generation of intracellular Ca²⁺ signals by a genetically encoded protein BACCS. Nat Commun 6: 8021, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
66.Jairaman A, Prakriya M. Molecular pharmacology of store-operated CRAC channels. Channels (Austin) 7: 402–414, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
67.Jha A, Ahuja M, Maleth J, Moreno CM, Yuan JP, Kim MS, Muallem S. The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function. J Cell Biol 202: 71–79, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
68.Ji W, Xu P, Li Z, Lu J, Liu L, Zhan Y, Chen Y, Hille B, Xu T, Chen L. Functional stoichiometry of the unitary calcium-release-activated calcium channel. Proc Natl Acad Sci USA 105: 13668–13673, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
69.Jing J, He L, Sun A, Quintana A, Ding Y, Ma G, Tan P, Liang X, Zheng X, Chen L, Shi X, Zhang SL, Zhong L, Huang Y, Dong MQ, Walker CL, Hogan PG, Wang Y, Zhou Y. Proteomic mapping of ER-PM junctions identifies STIMATE as a regulator of Ca influx. Nat Cell Biol 17: 1339–1347, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
70.Kar P, Parekh AB. Distinct spatial Ca²⁺ signatures selectively activate different NFAT transcription factor isoforms. Mol Cell 58: 232–243, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
71.Kawasaki T, Lange I, Feske S. A minimal regulatory domain in the C terminus of STIM1 binds to and activates ORAI1 CRAC channels. Biochem Biophys Res Commun 385: 49–54, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
72.Korzeniowski MK, Manjarres IM, Varnai P, Balla T. Activation of STIM1-Orai1 involves an intramolecular switching mechanism. Sci Signal 3: ra82, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
73.Korzeniowski MK, Popovic MA, Szentpetery Z, Varnai P, Stojilkovic SS, Balla T. Dependence of STIM1/Orai1-mediated calcium entry on plasma membrane phosphoinositides. J Biol Chem 284: 21027–21035, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
74.Lee KP, Yuan JP, Hong JH, So I, Worley PF, Muallem S. An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs. FEBS Lett 584: 2022–2027, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
75.Lee KP, Yuan JP, Zeng W, So I, Worley PF, Muallem S. Molecular determinants of fast Ca²⁺-dependent inactivation and gating of the Orai channels. Proc Natl Acad Sci USA 106: 14687–14692, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
76.Lepple-Wienhues A, Cahalan MD. Conductance and permeation of monovalent cations through depletion-activated Ca²⁺ channels (ICRAC) in Jurkat T cells. Biophys J 71: 787–794, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
77.Lewis RS. Store-operated calcium channels. Adv Second Messenger Phosphoprotein Res 33: 279–307, 1999. [DOI] [PubMed] [Google Scholar]
78.Lewis RS, Cahalan MD. Mitogen-induced oscillations of cytosolic Ca²⁺ and transmembrane Ca²⁺ current in human leukemic T cells. Cell Regul 1: 99–112, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Li Z, Liu L, Deng Y, Ji W, Du W, Xu P, Chen L, Xu T. Graded activation of CRAC channel by binding of different numbers of STIM1 to Orai1 subunits. Cell Res 21: 305–315, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
80.Li Z, Lu J, Xu P, Xie X, Chen L, Xu T. Mapping the interacting domains of STIM1 and Orai1 in Ca²⁺ release-activated Ca²⁺ channel activation. J Biol Chem 282: 29448–29456, 2007. [DOI] [PubMed] [Google Scholar]
81.Liao M, Cao E, Julius D, Cheng Y. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504: 107–112, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
83.Liou J, Fivaz M, Inoue T, Meyer T. Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca²⁺ store depletion. Proc Natl Acad Sci USA 104: 9301–9306, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
84.Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T. STIM is a Ca²⁺ sensor essential for Ca²⁺-store-depletion-triggered Ca²⁺ influx. Curr Biol 15: 1235–1241, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
85.Lioudyno MI, Kozak JA, Penna A, Safrina O, Zhang SL, Sen D, Roos J, Stauderman KA, Cahalan MD. Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation. Proc Natl Acad Sci USA 105: 2011–2016, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
86.Lis A, Peinelt C, Beck A, Parvez S, Monteilh-Zoller M, Fleig A, Penner R. CRACM1, CRACM2, and CRACM3 are store-operated Ca²⁺ channels with distinct functional properties. Curr Biol 17: 794–800, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
87.Lis A, Zierler S, Peinelt C, Fleig A, Penner R. A single lysine in the N-terminal region of store-operated channels is critical for STIM1-mediated gating. J Gen Physiol 136: 673–686, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
88.Litjens T, Harland ML, Roberts ML, Barritt GJ, Rychkov GY. Fast Ca²⁺-dependent inactivation of the store-operated Ca²⁺ current (I_SOC) in liver cells: a role for calmodulin. J Physiol 558: 85–97, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
89.Liu Y, Zheng X, Mueller GA, Sobhany M, DeRose EF, Zhang Y, London RE, Birnbaumer L. Crystal structure of calmodulin binding domain of orai1 in complex with Ca²⁺ calmodulin displays a unique binding mode. J Biol Chem 287: 43030–43041, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
90.Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454: 538–542, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
91.Luik RM, Wu MM, Buchanan J, Lewis RS. The elementary unit of store-operated Ca²⁺ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J Cell Biol 174: 815–825, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
92.Ma G, Wei M, He L, Liu C, Wu B, Zhang SL, Jing J, Liang X, Senes A, Tan P, Li S, Sun A, Bi Y, Zhong L, Si H, Shen Y, Li M, Lee MS, Zhou W, Wang J, Wang Y, Zhou Y. Inside-out Ca²⁺ signalling prompted by STIM1 conformational switch. Nat Commun 6: 7826, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
93.Madl J, Weghuber J, Fritsch R, Derler I, Fahrner M, Frischauf I, Lackner B, Romanin C, Schutz GJ. Resting state Orai1 diffuses as homotetramer in the plasma membrane of live mammalian cells. J Biol Chem 285: 41135–41142, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
94.Maleth J, Choi S, Muallem S, Ahuja M. Translocation between PI(4,5)P₂-poor and PI(4,5)P₂-rich microdomains during store depletion determines STIM1 conformation and Orai1 gating. Nat Commun 5: 5843, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
95.Manji SS, Parker NJ, Williams RT, van Stekelenburg L, Pearson RB, Dziadek M, Smith PJ. STIM1: a novel phosphoprotein located at the cell surface. Biochim Biophys Acta 1481: 147–155, 2000. [DOI] [PubMed] [Google Scholar]
96.Maruyama Y, Ogura T, Mio K, Kato K, Kaneko T, Kiyonaka S, Mori Y, Sato C. Tetrameric Orai1 is a teardrop-shaped molecule with a long, tapered cytoplasmic domain. J Biol Chem 284: 13676–13685, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
97.Mason JM, Hagemann UB, Arndt KM. Improved stability of the Jun-Fos Activator Protein-1 coiled coil motif: a stopped-flow circular dichroism kinetic analysis. J Biol Chem 282: 23015–23024, 2007. [DOI] [PubMed] [Google Scholar]
98.Maus M, Jairaman A, Stathopulos PB, Muik M, Fahrner M, Weidinger C, Benson M, Fuchs S, Ehl S, Romanin C, Ikura M, Prakriya M, Feske S. Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation. Proc Natl Acad Sci USA 112: 6206–6211, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
99.McNally BA, Prakriya M. Permeation, selectivity and gating in store-operated CRAC channels. J Physiol 590: 4179–4191, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
100.McNally BA, Somasundaram A, Jairaman A, Yamashita M, Prakriya M. The C- and N-terminal STIM1 binding sites on Orai1 are required for both trapping and gating CRAC channels. J Physiol 591: 2833–2850, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
101.McNally BA, Somasundaram A, Yamashita M, Prakriya M. Gated regulation of CRAC channel ion selectivity by STIM1. Nature 482: 241–245, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
102.McNally BA, Yamashita M, Engh A, Prakriya M. Structural determinants of ion permeation in CRAC channels. Proc Natl Acad Sci USA 106: 22516–22521, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
103.Mercer JC, Dehaven WI, Smyth JT, Wedel B, Boyles RR, Bird GS, Putney JW Jr. Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J Biol Chem 281: 24979–24990, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
104.Miederer AM, Alansary D, Schwar G, Lee PH, Jung M, Helms V, Niemeyer BA. A STIM2 splice variant negatively regulates store-operated calcium entry. Nat Commun 6: 6899, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
105.Mignen O, Thompson JL, Shuttleworth TJ. Orai1 subunit stoichiometry of the mammalian CRAC channel pore. J Physiol 586: 419–425, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
106.Misceo D, Holmgren A, Louch WE, Holme PA, Mizobuchi M, Morales RJ, De Paula AM, Stray-Pedersen A, Lyle R, Dalhus B, Christensen G, Stormorken H, Tjonnfjord GE, Frengen E. A dominant STIM1 mutation causes Stormorken syndrome. Hum Mutat 35: 556–564, 2014. [DOI] [PubMed] [Google Scholar]
107.Morin G, Bruechle NO, Singh AR, Knopp C, Jedraszak G, Elbracht M, Bremond-Gignac D, Hartmann K, Sevestre H, Deutz P, Herent D, Nurnberg P, Romeo B, Konrad K, Mathieu-Dramard M, Oldenburg J, Bourges-Petit E, Shen Y, Zerres K, Ouadid-Ahidouch H, Rochette J. Gain-of-function mutation in STIM1 (P.R304W) is associated with Stormorken syndrome. Hum Mutat 35: 1121–1132, 2014. [DOI] [PubMed] [Google Scholar]
108.Muallem S, Fimmel CJ, Pandol SJ, Sachs G. Regulation of free cytosolic Ca²⁺ in the peptic and parietal cells of the rabbit gastric gland. J Biol Chem 261: 2660–2667, 1986. [PubMed] [Google Scholar]
109.Muik M, Fahrner M, Derler I, Schindl R, Bergsmann J, Frischauf I, Groschner K, Romanin C. A cytosolic homomerization and a modulatory domain within STIM1 C terminus determine coupling to ORAI1 channels. J Biol Chem 284: 8421–8426, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
110.Muik M, Fahrner M, Schindl R, Stathopulos P, Frischauf I, Derler I, Plenk P, Lackner B, Groschner K, Ikura M, Romanin C. STIM1 couples to ORAI1 via an intramolecular transition into an extended conformation. EMBO J 30: 1678–1689, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
111.Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C. Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation. J Biol Chem 283: 8014–8022, 2008. [DOI] [PubMed] [Google Scholar]
112.Mullins FM, Park CY, Dolmetsch RE, Lewis RS. STIM1 and calmodulin interact with Orai1 to induce Ca²⁺-dependent inactivation of CRAC channels. Proc Natl Acad Sci USA 106: 15495–15500, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
113.Navarro-Borelly L, Somasundaram A, Yamashita M, Ren D, Miller RJ, Prakriya M. STIM1-Orai1 interactions and Orai1 conformational changes revealed by live-cell FRET microscopy. J Physiol 586: 5383–5401, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
114.Nesin V, Wiley G, Kousi M, Ong EC, Lehmann T, Nicholl DJ, Suri M, Shahrizaila N, Katsanis N, Gaffney PM, Wierenga KJ, Tsiokas L. Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proc Natl Acad Sci USA 111: 4197–4202, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
115.Palty R, Isacoff EY. Cooperative binding of stromal interaction molecule 1 (STIM1) to the N and C termini of calcium release-activated calcium modulator 1 (Orai1). J Biol Chem 291: 334–341, 2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
116.Palty R, Raveh A, Kaminsky I, Meller R, Reuveny E. SARAF inactivates the store operated calcium entry machinery to prevent excess calcium refilling. Cell 149: 425–438, 2012. [DOI] [PubMed] [Google Scholar]
117.Palty R, Stanley C, Isacoff EY. Critical role for Orai1 C-terminal domain and TM4 in CRAC channel gating. Cell Res 25: 963–980, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
118.Parekh AB. Store-operated channels: mechanisms and function. J Physiol 586: 3033, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
119.Parekh AB. Store-operated CRAC channels: function in health and disease. Nat Rev Drug Discov 9: 399–410, 2010. [DOI] [PubMed] [Google Scholar]
120.Parekh AB, Putney JW Jr. Store-operated calcium channels. Physiol Rev 85: 757–810, 2005. [DOI] [PubMed] [Google Scholar]
121.Park CY, Hoover PJ, Mullins FM, Bachhawat P, Covington ED, Raunser S, Walz T, Garcia KC, Dolmetsch RE, Lewis RS. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136: 876–890, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
122.Payandeh J, Scheuer T, Zheng N, Catterall WA. The crystal structure of a voltage-gated sodium channel. Nature 475: 353–358, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
123.Peinelt C, Vig M, Koomoa DL, Beck A, Nadler MJ, Koblan-Huberson M, Lis A, Fleig A, Penner R, Kinet JP. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol 8: 771–773, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
124.Penna A, Demuro A, Yeromin AV, Zhang SL, Safrina O, Parker I, Cahalan MD. The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature 456: 116–120, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
125.Penner R, Matthews G, Neher E. Regulation of calcium influx by second messengers in rat mast cells. Nature 334: 499–504, 1988. [DOI] [PubMed] [Google Scholar]
126.Pozo-Guisado E, Campbell DG, Deak M, Alvarez-Barrientos A, Morrice NA, Alvarez IS, Alessi DR, Martin-Romero FJ. Phosphorylation of STIM1 at ERK1/2 target sites modulates store-operated calcium entry. J Cell Sci 123: 3084–3093, 2010. [DOI] [PubMed] [Google Scholar]
127.Pozo-Guisado E, Casas-Rua V, Tomas-Martin P, Lopez-Guerrero AM, Alvarez-Barrientos A, Martin-Romero FJ. Phosphorylation of STIM1 at ERK1/2 target sites regulates interaction with the microtubule plus-end binding protein EB1. J Cell Sci 126: 3170–3180, 2013. [DOI] [PubMed] [Google Scholar]
128.Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG. Orai1 is an essential pore subunit of the CRAC channel. Nature 443: 230–233, 2006. [DOI] [PubMed] [Google Scholar]
129.Prakriya M, Lewis RS. CRAC channels: activation, permeation, and the search for a molecular identity. Cell Calcium 33: 311–321, 2003. [DOI] [PubMed] [Google Scholar]
130.Prakriya M, Lewis RS. Regulation of CRAC channel activity by recruitment of silent channels to a high open-probability gating mode. J Gen Physiol 128: 373–386, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
131.Prakriya M, Lewis RS. Separation and characterization of currents through store-operated CRAC channels and Mg²⁺-inhibited cation (MIC) channels. J Gen Physiol 119: 487–507, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
132.Prakriya M, Lewis RS. Store-operated calcium channels. Physiol Rev 95: 1383–1436, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
133.Putney JW. Pharmacology of store-operated calcium channels. Mol Interv 10: 209–218, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
134.Putney JW., Jr A model for receptor-regulated calcium entry. Cell Calcium 7: 1–12, 1986. [DOI] [PubMed] [Google Scholar]
135.Quintana A, Rajanikanth V, Farber-Katz S, Gudlur A, Zhang C, Jing J, Zhou Y, Rao A, Hogan PG. TMEM110 regulates the maintenance and remodeling of mammalian ER-plasma membrane junctions competent for STIM-ORAI signaling. Proc Natl Acad Sci USA 112: E7083–E7092, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
136.Rana A, Yen M, Sadaghiani AM, Malmersjo S, Park CY, Dolmetsch RE, Lewis RS. Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels. J Cell Biol 209: 653–669, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
137.Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA. STIM1, an essential and conserved component of store-operated Ca²⁺ channel function. J Cell Biol 169: 435–445, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
138.Rothberg BS, Wang Y, Gill DL. Orai channel pore properties and gating by STIM: implications from the Orai crystal structure. Sci Signal 6: pe9, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
139.Salido GM, Sage SO, Rosado JA. Biochemical and functional properties of the store-operated Ca²⁺ channels. Cell Signal 21: 457–461, 2009. [DOI] [PubMed] [Google Scholar]
140.Sather WA, McCleskey EW. Permeation and selectivity in calcium channels. Annu Rev Physiol 65: 133–159, 2003. [DOI] [PubMed] [Google Scholar]
141.Sauc S, Bulla M, Nunes P, Orci L, Marchetti A, Antigny F, Bernheim L, Cosson P, Frieden M, Demaurex N. STIM1L traps and gates Orai1 channels without remodeling the cortical ER. J Cell Sci 128: 1568–1579, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
142.Schindl R, Frischauf I, Bergsmann J, Muik M, Derler I, Lackner B, Groschner K, Romanin C. Plasticity in Ca²⁺ selectivity of Orai1/Orai3 heteromeric channel. Proc Natl Acad Sci USA 106: 19623–19628, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
143.Schindl R, Muik M, Fahrner M, Derler I, Fritsch R, Bergsmann J, Romanin C. Recent progress on STIM1 domains controlling Orai activation. Cell Calcium 46: 227–232, 2009. [DOI] [PubMed] [Google Scholar]
144.Schulz I, Schnefel S, Banfic H, Eckhardt L. Ca²⁺ signalling in exocrine glands in comparison to that in vascular smooth muscle cells. Ann NY Acad Sci 488: 240–251, 1986. [DOI] [PubMed] [Google Scholar]
145.Scrimgeour N, Litjens T, Ma L, Barritt GJ, Rychkov GY. Properties of Orai1 mediated store-operated current depend on the expression levels of STIM1 and Orai1 proteins. J Physiol 587: 2903–2918, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
146.Scrimgeour NR, Wilson DP, Barritt GJ, Rychkov GY. Structural and stoichiometric determinants of Ca²⁺ release-activated Ca²⁺ (CRAC) channel Ca²⁺-dependent inactivation. Biochim Biophys Acta 1838: 1281–1287, 2014. [DOI] [PubMed] [Google Scholar]
147.Sharma S, Quintana A, Findlay GM, Mettlen M, Baust B, Jain M, Nilsson R, Rao A, Hogan PG. An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca²⁺ entry. Nature 499: 238–242, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
148.Shuttleworth TJ. Orai3—the “exceptional” Orai? J Physiol 590: 241–257, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
149.Smyth JT, Dehaven WI, Bird GS, Putney JW Jr. Ca²⁺-store-dependent and -independent reversal of Stim1 localization and function. J Cell Sci 121: 762–772, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
150.Soboloff J, Rothberg BS, Madesh M, Gill DL. STIM proteins: dynamic calcium signal transducers. Nat Rev Mol Cell Biol 13: 549–565, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
151.Soboloff J, Spassova MA, Hewavitharana T, He LP, Xu W, Johnstone LS, Dziadek MA, Gill DL. STIM2 is an inhibitor of STIM1-mediated store-operated Ca²⁺ entry. Curr Biol 16: 1465–1470, 2006. [DOI] [PubMed] [Google Scholar]
152.Soboloff J, Spassova MA, Tang XD, Hewavitharana T, Xu W, Gill DL. Orai1 and STIM reconstitute store-operated calcium channel function. J Biol Chem 281: 20661–20665, 2006. [DOI] [PubMed] [Google Scholar]
153.Spassova MA, Soboloff J, He LP, Xu W, Dziadek MA, Gill DL. STIM1 has a plasma membrane role in the activation of store-operated Ca²⁺ channels. Proc Natl Acad Sci USA 103: 4040–4045, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
154.Srikanth S, Jew M, Kim KD, Yee MK, Abramson J, Gwack Y. Junctate is a Ca²⁺-sensing structural component of Orai1 and stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci USA 109: 8682–8687, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
155.Srikanth S, Jung HJ, Kim KD, Souda P, Whitelegge J, Gwack Y. A novel EF-hand protein, CRACR2A, is a cytosolic Ca²⁺ sensor that stabilizes CRAC channels in T cells. Nat Cell Biol 12: 436–446, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
156.Srikanth S, Jung HJ, Ribalet B, Gwack Y. The intracellular loop of Orai1 plays a central role in fast inactivation of Ca²⁺ release-activated Ca²⁺ channels. J Biol Chem 285: 5066–5075. [DOI] [PMC free article] [PubMed] [Google Scholar]
157.Srikanth S, Yee MK, Gwack Y, Ribalet B. The third transmembrane segment of orai1 protein modulates Ca²⁺ release-activated Ca²⁺ (CRAC) channel gating and permeation properties. J Biol Chem 286: 35318–35328, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
158.Stathopulos PB, Ikura M. Partial unfolding and oligomerization of stromal interaction molecules as an initiation mechanism of store operated calcium entry. Biochem Cell Biol 88: 175–183, 2010. [DOI] [PubMed] [Google Scholar]
159.Stathopulos PB, Ikura M. Structural aspects of calcium-release activated calcium channel function. Channels (Austin) 7: 344–353, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
160.Stathopulos PB, Li GY, Plevin MJ, Ames JB, Ikura M. Stored Ca²⁺ depletion-induced oligomerization of stromal interaction molecule 1 (STIM1) via the EF-SAM region: an initiation mechanism for capacitive Ca²⁺ entry. J Biol Chem 281: 35855–35862, 2006. [DOI] [PubMed] [Google Scholar]
161.Stathopulos PB, Schindl R, Fahrner M, Zheng L, Gasmi-Seabrook GM, Muik M, Romanin C, Ikura M. STIM1/Orai1 coiled-coil interplay in the regulation of store-operated calcium entry. Nat Commun 4: 2963, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
162.Stathopulos PB, Zheng L, Li GY, Plevin MJ, Ikura M. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell 135: 110–122, 2008. [DOI] [PubMed] [Google Scholar]
163.Streb H, Irvine RF, Berridge MJ, Schulz I. Release of Ca²⁺ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature 306: 67–69, 1983. [DOI] [PubMed] [Google Scholar]
164.Su Z, Shoemaker RL, Marchase RB, Blalock JE. Ca²⁺ modulation of Ca²⁺ release-activated Ca²⁺ channels is responsible for the inactivation of its monovalent cation current. Biophys J 86: 805–814, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
165.Tamura N, Draviam VM. Microtubule plus-ends within a mitotic cell are “moving platforms” with anchoring, signalling and force-coupling roles. Open Biol 2: 120132, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
166.Tirado-Lee L, Yamashita M, Prakriya M. Conformational changes in the Orai1 C-terminus evoked by STIM1 binding. PLoS One 10: e0128622, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
167.Treves S, Franzini-Armstrong C, Moccagatta L, Arnoult C, Grasso C, Schrum A, Ducreux S, Zhu MX, Mikoshiba K, Girard T, Smida-Rezgui S, Ronjat M, Zorzato F. Junctate is a key element in calcium entry induced by activation of InsP₃ receptors and/or calcium store depletion. J Cell Biol 166: 537–548, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
168.Treves S, Vukcevic M, Griesser J, Armstrong CF, Zhu MX, Zorzato F. Agonist-activated Ca²⁺ influx occurs at stable plasma membrane and endoplasmic reticulum junctions. J Cell Sci 123: 4170–4181, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
169.Vig M, Beck A, Billingsley JM, Lis A, Parvez S, Peinelt C, Koomoa DL, Soboloff J, Gill DL, Fleig A, Kinet JP, Penner R. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr Biol 16: 2073–2079, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
170.Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP. CRACM1 is a plasma membrane protein essential for store-operated Ca²⁺ entry. Science 312: 1220–1223, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
172.Walsh CM, Chvanov M, Haynes LP, Petersen OH, Tepikin AV, Burgoyne RD. Role of phosphoinositides in STIM1 dynamics and store-operated calcium entry. Biochem J 425: 159–168, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
173.Wang X, Wang Y, Zhou Y, Hendron E, Mancarella S, Andrake MD, Rothberg BS, Soboloff J, Gill DL. Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site. Nat Commun 5: 3183, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
174.Watanabe T, Noritake J, Kakeno M, Matsui T, Harada T, Wang S, Itoh N, Sato K, Matsuzawa K, Iwamatsu A, Galjart N, Kaibuchi K. Phosphorylation of CLASP2 by GSK-3beta regulates its interaction with IQGAP1, EB1 and microtubules. J Cell Sci 122: 2969–2979, 2009. [DOI] [PubMed] [Google Scholar]
175.Webster SM, Del Camino D, Dekker JP, Yellen G. Intracellular gate opening in Shaker K⁺ channels defined by high-affinity metal bridges. Nature 428: 864–868, 2004. [DOI] [PubMed] [Google Scholar]
176.Williams RT, Senior PV, Van Stekelenburg L, Layton JE, Smith PJ, Dziadek MA. Stromal interaction molecule 1 (STIM1), a transmembrane protein with growth suppressor activity, contains an extracellular SAM domain modified by N-linked glycosylation. Biochim Biophys Acta 1596: 131–137, 2002. [DOI] [PubMed] [Google Scholar]
177.Wissenbach U, Philipp SE, Gross SA, Cavalie A, Flockerzi V. Primary structure, chromosomal localization and expression in immune cells of the murine ORAI and STIM genes. Cell Calcium 42: 439–446, 2007. [DOI] [PubMed] [Google Scholar]
178.Wu MM, Buchanan J, Luik RM, Lewis RS. Ca²⁺ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J Cell Biol 174: 803–813, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
179.Yamashita M, Navarro-Borelly L, McNally BA, Prakriya M. Orai1 mutations alter ion permeation and Ca²⁺-dependent fast inactivation of CRAC channels: evidence for coupling of permeation and gating. J Gen Physiol 130: 525–540, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
180.Yang X, Jin H, Cai X, Li S, Shen Y. Structural and mechanistic insights into the activation of Stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci USA 109: 5657–5662, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
181.Yeromin AV, Zhang SL, Jiang W, Yu Y, Safrina O, Cahalan MD. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443: 226–229, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
182.Yu J, Zhang H, Zhang M, Deng Y, Wang H, Lu J, Xu T, Xu P. An aromatic amino acid in the coiled-coil 1 domain plays a crucial role in the auto-inhibitory mechanism of STIM1. Biochem J 454: 401–409, 2013. [DOI] [PubMed] [Google Scholar]
183.Yuan JP, Zeng W, Dorwart MR, Choi YJ, Worley PF, Muallem S. SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat Cell Biol 11: 337–343, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
184.Zhang SL, Yeromin AV, Hu J, Amcheslavsky A, Zheng H, Cahalan MD. Mutations in Orai1 transmembrane segment 1 cause STIM1-independent activation of Orai1 channels at glycine 98 and channel closure at arginine 91. Proc Natl Acad Sci USA 108: 17838–17843, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
185.Zhang SL, Yeromin AV, Zhang XH, Yu Y, Safrina O, Penna A, Roos J, Stauderman KA, Cahalan MD. Genome-wide RNAi screen of Ca²⁺ influx identifies genes that regulate Ca²⁺ release-activated Ca²⁺ channel activity. Proc Natl Acad Sci USA 103: 9357–9362, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
186.Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD. STIM1 is a Ca²⁺ sensor that activates CRAC channels and migrates from the Ca²⁺ store to the plasma membrane. Nature 437: 902–905, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
187.Zhang X, Zhang W, Gonzalez-Cobos JC, Jardin I, Romanin C, Matrougui K, Trebak M. Complex role of STIM1 in the activation of store-independent Orai1/3 channels. J Gen Physiol 143: 345–359, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
188.Zhao Y, Yarov-Yarovoy V, Scheuer T, Catterall WA. A gating hinge in Na⁺ channels; a molecular switch for electrical signaling. Neuron 41: 859–865, 2004. [DOI] [PubMed] [Google Scholar]
189.Zheng H, Zhou MH, Hu C, Kuo E, Peng X, Hu J, Kuo L, Zhang SL. Differential roles of the C and N termini of Orai1 protein in interacting with stromal interaction molecule 1 (STIM1) for Ca²⁺ release-activated Ca²⁺ (CRAC) channel activation. J Biol Chem 288: 11263–11272, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
190.Zheng L, Stathopulos PB, Schindl R, Li GY, Romanin C, Ikura M. Auto-inhibitory role of the EF-SAM domain of STIM proteins in store-operated calcium entry. Proc Natl Acad Sci USA 108: 1337–1342, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
191.Zhou Y, Meraner P, Kwon HT, Machnes D, Oh-hora M, Zimmer J, Huang Y, Stura A, Rao A, Hogan PG. STIM1 gates the store-operated calcium channel ORAI1 in vitro. Nat Struct Mol Biol 17: 112–116, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
192.Zhou Y, Ramachandran S, Oh-Hora M, Rao A, Hogan PG. Pore architecture of the ORAI1 store-operated calcium channel. Proc Natl Acad Sci USA 107: 4896–4901, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
193.Zhou Y, Srinivasan P, Razavi S, Seymour S, Meraner P, Gudlur A, Stathopulos PB, Ikura M, Rao A, Hogan PG. Initial activation of STIM1, the regulator of store-operated calcium entry. Nat Struct Mol Biol 20: 973–981, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
194.Zhou Y, Wang X, Wang X, Loktionova NA, Cai X, Nwokonko RM, Vrana E, Wang Y, Rothberg BS, Gill DL. STIM1 dimers undergo unimolecular coupling to activate Orai1 channels. Nat Commun 6: 8395, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]
195.Zumbrunn J, Kinoshita K, Hyman AA, Nathke IS. Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3 beta phosphorylation. Curr Biol 11: 44–49, 2001. [DOI] [PubMed] [Google Scholar]
196.Zweifach A, Lewis RS. Mitogen-regulated Ca²⁺ current of T lymphocytes is activated by depletion of intracellular Ca²⁺ stores. Proc Natl Acad Sci USA 90: 6295–6299, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
197.Zweifach A, Lewis RS. Rapid inactivation of depletion-activated calcium current (I_CRAC) due to local calcium feedback. J Gen Physiol 105: 209–226, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B1] 1.Altin JG, Bygrave FL. Second messengers and the regulation of Ca²⁺ fluxes by Ca²⁺-mobilizing agonists in rat liver. Biol Rev Camb Philos Soc 63: 551–611, 1988. [DOI] [PubMed] [Google Scholar]

[B2] 2.Ambily A, Kaiser WJ, Pierro C, Chamberlain EV, Li Z, Jones CI, Kassouf N, Gibbins JM, Authi KS. The role of plasma membrane STIM1 and Ca²⁺ entry in platelet aggregation. STIM1 binds to novel proteins in human platelets. Cell Signal 26: 502–511, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B3] 3.Ambudkar IS. TRPC1: a core component of store-operated calcium channels. Biochem Soc Trans 35: 96–100, 2007. [DOI] [PubMed] [Google Scholar]

[B4] 4.Amcheslavsky A, Safrina O, Cahalan MD. Orai3 TM3 point mutation G158C alters kinetics of 2-APB-induced gating by disulfide bridge formation with TM2 C101. J Gen Physiol 142: 405–412, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B5] 5.Amcheslavsky A, Wood ML, Yeromin AV, Parker I, Freites JA, Tobias DJ, Cahalan MD. Molecular biophysics of Orai store-operated Ca²⁺ channels. Biophys J 108: 237–246, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B6] 6.Baba Y, Hayashi K, Fujii Y, Mizushima A, Watarai H, Wakamori M, Numaga T, Mori Y, Iino M, Hikida M, Kurosaki T. Coupling of STIM1 to store-operated Ca²⁺ entry through its constitutive and inducible movement in the endoplasmic reticulum. Proc Natl Acad Sci USA 103: 16704–16709, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B7] 7.Bai XC, McMullan G, Scheres SH. How cryo-EM is revolutionizing structural biology. Trends Biochem Sci 40: 49–57, 2015. [DOI] [PubMed] [Google Scholar]

[B8] 8.Bakowski D, Parekh AB. Permeation through store-operated CRAC channels in divalent-free solution: potential problems and implications for putative CRAC channel genes. Cell Calcium 32: 379–391, 2002. [DOI] [PubMed] [Google Scholar]

[B9] 9.Barr VA, Bernot KM, Srikanth S, Gwack Y, Balagopalan L, Regan CK, Helman DJ, Sommers CL, Oh-Hora M, Rao A, Samelson LE. Dynamic movement of the calcium sensor STIM1 and the calcium channel Orai1 in activated T-cells: puncta and distal caps. Mol Biol Cell 19: 2802–2817, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B10] 10.Bergsmann J, Derler I, Muik M, Frischauf I, Fahrner M, Pollheimer P, Schwarzinger C, Gruber HJ, Groschner K, Romanin C. Molecular determinants within N terminus of Orai3 protein that control channel activation and gating. J Biol Chem 286: 31565–31575, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B11] 11.Berna-Erro A, Redondo PC, Rosado JA. Store-operated Ca²⁺ entry. Adv Exp Med Biol 740: 349–382, 2012. [DOI] [PubMed] [Google Scholar]

[B12] 12.Berna-Erro A, Woodard GE, Rosado JA. Orais and STIMs: physiological mechanisms and disease. J Cell Mol Med 16: 407–424, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B13] 13.Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4: 517–529, 2003. [DOI] [PubMed] [Google Scholar]

[B14] 14.Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol 1: 11–21, 2000. [DOI] [PubMed] [Google Scholar]

[B15] 15.Bogeski I, Al-Ansary D, Qu B, Niemeyer BA, Hoth M, Peinelt C. Pharmacology of ORAI channels as a tool to understand their physiological functions. Expert Rev Clin Pharmacol 3: 291–303, 2010. [DOI] [PubMed] [Google Scholar]

[B16] 16.Bogeski I, Kilch T, Niemeyer BA. ROS and SOCE: recent advances and controversies in the regulation of STIM and Orai. J Physiol 590: 4193–4200, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B17] 17.Brandman O, Liou J, Park WS, Meyer T. STIM2 is a feedback regulator that stabilizes basal cytosolic and endoplasmic reticulum Ca²⁺ levels. Cell 131: 1327–1339, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B18] 18.Cahalan MD. STIMulating store-operated Ca²⁺ entry. Nat Cell Biol 11: 669–677, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B19] 19.Cahalan MD, Chandy KG. The functional network of ion channels in T lymphocytes. Immunol Rev 231: 59–87, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B20] 20.Cai X. Molecular evolution and functional divergence of the Ca²⁺ sensor protein in store-operated Ca²⁺ entry: stromal interaction molecule. PLoS One 2: e609, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B21] 21.Calloway N, Holowka D, Baird B. A basic sequence in STIM1 promotes Ca²⁺ influx by interacting with the C-terminal acidic coiled coil of Orai1. Biochemistry 49: 1067–1071, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B22] 22.Calloway N, Vig M, Kinet JP, Holowka D, Baird B. Molecular clustering of STIM1 with Orai1/CRACM1 at the plasma membrane depends dynamically on depletion of Ca²⁺ stores and on electrostatic interactions. Mol Biol Cell 20: 389–399, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B23] 23.Cao X, Choi S, Maleth JJ, Park S, Ahuja M, Muallem S. The ER/PM microdomain, PI(4,5)P₂ and the regulation of STIM1-Orai1 channel function. Cell Calcium 58: 342–348, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B24] 24.Chang CL, Hsieh TS, Yang TT, Rothberg KG, Azizoglu DB, Volk E, Liao JC, Liou J. Feedback regulation of receptor-induced Ca²⁺ signaling mediated by E-Syt1 and Nir2 at endoplasmic reticulum-plasma membrane junctions. Cell Rep 5: 813–825, 2013. [DOI] [PubMed] [Google Scholar]

[B25] 25.Cheng Y. Single-particle cryo-EM at crystallographic resolution. Cell 161: 450–457, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B26] 26.Chvanov M, Walsh CM, Haynes LP, Voronina SG, Lur G, Gerasimenko OV, Barraclough R, Rudland PS, Petersen OH, Burgoyne RD, Tepikin AV. ATP depletion induces translocation of STIM1 to puncta and formation of STIM1-ORAI1 clusters: translocation and re-translocation of STIM1 does not require ATP. Pflügers Arch 457: 505–517, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B27] 27.Collins SR, Meyer T. Evolutionary origins of STIM1 and STIM2 within ancient Ca²⁺ signaling systems. Trends Cell Biol 21: 202–211, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B28] 28.Covington ED, Wu MM, Lewis RS. Essential role for the CRAC activation domain in store-dependent oligomerization of STIM1. Mol Biol Cell 21: 1897–1907, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B29] 29.Cui B, Yang X, Li S, Lin Z, Wang Z, Dong C, Shen Y. The inhibitory helix controls the intramolecular conformational switching of the C-terminus of STIM1. PLoS One 8: e74735, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B30] 30.Darbellay B, Arnaudeau S, Bader CR, Konig S, Bernheim L. STIM1L is a new actin-binding splice variant involved in fast repetitive Ca²⁺ release. J Cell Biol 194: 335–346, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B31] 31.Demuro A, Penna A, Safrina O, Yeromin AV, Amcheslavsky A, Cahalan MD, Parker I. Subunit stoichiometry of human Orai1 and Orai3 channels in closed and open states. Proc Natl Acad Sci USA 108: 17832–17837, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B32] 32.Derler I, Fahrner M, Carugo O, Muik M, Bergsmann J, Schindl R, Frischauf I, Eshaghi S, Romanin C. Increased hydrophobicity at the N terminus/membrane interface impairs gating of the severe combined immunodeficiency-related ORAI1 mutant. J Biol Chem 284: 15903–15915, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B33] 33.Derler I, Fahrner M, Muik M, Lackner B, Schindl R, Groschner K, Romanin CA. Ca²⁺ release-activated Ca²⁺ (CRAC) modulatory domain (CMD) within STIM1 mediates fast Ca²⁺-dependent inactivation of ORAI1 channels. J Biol Chem 284: 24933–24938, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B34] 34.Derler I, Madl J, Schutz G, Romanin C. Structure, regulation and biophysics of I_CRAC, STIM/Orai1. Adv Exp Med Biol 740: 383–410, 2012. [DOI] [PubMed] [Google Scholar]

[B35] 35.Derler I, Plenk P, Fahrner M, Muik M, Jardin I, Schindl R, Gruber HJ, Groschner K, Romanin C. The extended transmembrane Orai1 N-terminal (ETON) region combines binding interface and gate for Orai1 activation by STIM1. J Biol Chem 288: 29025–29034, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B36] 36.Derler I, Schindl R, Fritsch R, Romanin C. Gating and permeation of Orai channels. Front Biosci (Landmark Ed) 17: 1304–1322, 2012. [DOI] [PubMed] [Google Scholar]

[B37] 37.Dong H, Fiorin G, Carnevale V, Treptow W, Klein ML. Pore waters regulate ion permeation in a calcium release-activated calcium channel. Proc Natl Acad Sci USA 110: 17332–17337, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B38] 38.Dong H, Sharma M, Zhou HX, Cross TA. Glycines: role in alpha-helical membrane protein structures and a potential indicator of native conformation. Biochemistry 51: 4779–4789, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B39] 39.Dynes JL, Amcheslavsky A, Cahalan MD. Genetically targeted single-channel optical recording reveals multiple Orai1 gating states and oscillations in calcium influx. Proc Natl Acad Sci USA 113: 440–445, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B40] 40.Endo Y, Noguchi S, Hara Y, Hayashi YK, Motomura K, Miyatake S, Murakami N, Tanaka S, Yamashita S, Kizu R, Bamba M, Goto Y, Matsumoto N, Nonaka I, Nishino I. Dominant mutations in ORAI1 cause tubular aggregate myopathy with hypocalcemia via constitutive activation of store-operated Ca²⁺ channels. Hum Mol Genet 24: 637–648, 2015. [DOI] [PubMed] [Google Scholar]

[B41] 41.Ercan E, Momburg F, Engel U, Temmerman K, Nickel W, Seedorf M. A conserved, lipid-mediated sorting mechanism of yeast Ist2 and mammalian STIM proteins to the peripheral ER. Traffic 10: 1802–1818, 2009. [DOI] [PubMed] [Google Scholar]

[B42] 42.Fahrner M, Derler I, Jardin I, Romanin C. The STIM1/Orai signaling machinery. Channels (Austin) 7: 330–343, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B43] 43.Fahrner M, Muik M, Derler I, Schindl R, Fritsch R, Frischauf I, Romanin C. Mechanistic view on domains mediating STIM1-Orai coupling. Immunol Rev 231: 99–112, 2009. [DOI] [PubMed] [Google Scholar]

[B44] 44.Fahrner M, Muik M, Schindl R, Butorac C, Stathopulos P, Zheng L, Jardin I, Ikura M, Romanin C. A coiled-coil clamp controls both conformation and clustering of stromal interaction molecule 1 (STIM1). J Biol Chem 289: 33231–33244, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B45] 45.Fan G, Baker ML, Wang Z, Baker MR, Sinyagovskiy PA, Chiu W, Ludtke SJ, Serysheva II. Gating machinery of InsP₃R channels revealed by electron cryomicroscopy. Nature 527: 336–341, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B46] 46.Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441: 179–185, 2006. [DOI] [PubMed] [Google Scholar]

[B47] 47.Feske S, Skolnik EY, Prakriya M. Ion channels and transporters in lymphocyte function and immunity. Nat Rev Immunol 12: 532–547, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B48] 48.Frischauf I, Muik M, Derler I, Bergsmann J, Fahrner M, Schindl R, Groschner K, Romanin C. Molecular determinants of the coupling between STIM1 and Orai channels: differential activation of Orai1-3 channels by a STIM1 coiled-coil mutant. J Biol Chem 284: 21696–21706, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B49] 49.Frischauf I, Schindl R, Bergsmann J, Derler I, Fahrner M, Muik M, Fritsch R, Lackner B, Groschner K, Romanin C. Cooperativeness of Orai cytosolic domains tunes subtype-specific gating. J Biol Chem 286: 8577–8584, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B50] 50.Frischauf I, Schindl R, Derler I, Bergsmann J, Fahrner M, Romanin C. The STIM/Orai coupling machinery. Channels (Austin) 2: 261–268, 2008. [DOI] [PubMed] [Google Scholar]

[B51] 51.Frischauf I, Zayats V, Deix M, Hochreiter A, Jardin I, Muik M, Lackner B, Svobodova B, Pammer T, Litvinukova M, Sridhar AA, Derler I, Bogeski I, Romanin C, Ettrich RH, Schindl R. A calcium-accumulating region, CAR, in the channel Orai1 enhances Ca²⁺ permeation and SOCE-induced gene transcription. Sci Signal 8: ra131, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B52] 52.Giordano F, Saheki Y, Idevall-Hagren O, Colombo SF, Pirruccello M, Milosevic I, Gracheva EO, Bagriantsev SN, Borgese N, De Camilli P. PI(4,5)P₂-dependent and Ca²⁺-regulated ER-PM interactions mediated by the extended synaptotagmins. Cell 153: 1494–1509, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B53] 53.Grigoriev I, Gouveia SM, van der Vaart B, Demmers J, Smyth JT, Honnappa S, Splinter D, Steinmetz MO, Putney JW Jr, Hoogenraad CC, Akhmanova A. STIM1 is a MT-plus-end-tracking protein involved in remodeling of the ER. Curr Biol 18: 177–182, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B54] 54.Gudlur A, Quintana A, Zhou Y, Hirve N, Mahapatra S, Hogan PG. STIM1 triggers a gating rearrangement at the extracellular mouth of the ORAI1 channel. Nat Commun 5: 5164, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B55] 55.He L, Zhang Y, Ma G, Tan P, Li Z, Zang S, Wu X, Jing J, Fang S, Zhou L, Wang Y, Huang Y, Hogan PG, Han G, Zhou Y. Near-infrared photoactivatable control of Ca²⁺ signaling and optogenetic immunomodulation. eLife 4: 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B56] 56.Hewavitharana T, Deng X, Soboloff J, Gill DL. Role of STIM and Orai proteins in the store-operated calcium signaling pathway. Cell Calcium 42: 173–182, 2007. [DOI] [PubMed] [Google Scholar]

[B57] 57.Hogan PG, Lewis RS, Rao A. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu Rev Immunol 28: 491–533, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B58] 58.Hogan PG, Rao A. Store-operated calcium entry: mechanisms and modulation. Biochem Biophys Res Commun 460: 40–49, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B59] 59.Hoover PJ, Lewis RS. Stoichiometric requirements for trapping and gating of Ca²⁺ release-activated Ca²⁺ (CRAC) channels by stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci USA 108: 13299–13304, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B60] 60.Hoth M, Niemeyer BA. The neglected CRAC proteins: Orai2, Orai3, and STIM2. Curr Top Membr 71: 237–271, 2013. [DOI] [PubMed] [Google Scholar]

[B61] 61.Hoth M, Penner R. Calcium release-activated calcium current in rat mast cells. J Physiol 465: 359–386, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B62] 62.Hoth M, Penner R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature 355: 353–356, 1992. [DOI] [PubMed] [Google Scholar]

[B63] 63.Hou X, Pedi L, Diver MM, Long SB. Crystal structure of the calcium release-activated calcium channel Orai. Science 338: 1308–1313, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B64] 64.Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF. STIM1 carboxyl-terminus activates native SOC, I_crac and TRPC1 channels. Nat Cell Biol 8: 1003–1010, 2006. [DOI] [PubMed] [Google Scholar]

[B65] 65.Ishii T, Sato K, Kakumoto T, Miura S, Touhara K, Takeuchi S, Nakata T. Light generation of intracellular Ca²⁺ signals by a genetically encoded protein BACCS. Nat Commun 6: 8021, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B66] 66.Jairaman A, Prakriya M. Molecular pharmacology of store-operated CRAC channels. Channels (Austin) 7: 402–414, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B67] 67.Jha A, Ahuja M, Maleth J, Moreno CM, Yuan JP, Kim MS, Muallem S. The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function. J Cell Biol 202: 71–79, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B68] 68.Ji W, Xu P, Li Z, Lu J, Liu L, Zhan Y, Chen Y, Hille B, Xu T, Chen L. Functional stoichiometry of the unitary calcium-release-activated calcium channel. Proc Natl Acad Sci USA 105: 13668–13673, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B69] 69.Jing J, He L, Sun A, Quintana A, Ding Y, Ma G, Tan P, Liang X, Zheng X, Chen L, Shi X, Zhang SL, Zhong L, Huang Y, Dong MQ, Walker CL, Hogan PG, Wang Y, Zhou Y. Proteomic mapping of ER-PM junctions identifies STIMATE as a regulator of Ca influx. Nat Cell Biol 17: 1339–1347, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B70] 70.Kar P, Parekh AB. Distinct spatial Ca²⁺ signatures selectively activate different NFAT transcription factor isoforms. Mol Cell 58: 232–243, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B71] 71.Kawasaki T, Lange I, Feske S. A minimal regulatory domain in the C terminus of STIM1 binds to and activates ORAI1 CRAC channels. Biochem Biophys Res Commun 385: 49–54, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B72] 72.Korzeniowski MK, Manjarres IM, Varnai P, Balla T. Activation of STIM1-Orai1 involves an intramolecular switching mechanism. Sci Signal 3: ra82, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B73] 73.Korzeniowski MK, Popovic MA, Szentpetery Z, Varnai P, Stojilkovic SS, Balla T. Dependence of STIM1/Orai1-mediated calcium entry on plasma membrane phosphoinositides. J Biol Chem 284: 21027–21035, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B74] 74.Lee KP, Yuan JP, Hong JH, So I, Worley PF, Muallem S. An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs. FEBS Lett 584: 2022–2027, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B75] 75.Lee KP, Yuan JP, Zeng W, So I, Worley PF, Muallem S. Molecular determinants of fast Ca²⁺-dependent inactivation and gating of the Orai channels. Proc Natl Acad Sci USA 106: 14687–14692, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B76] 76.Lepple-Wienhues A, Cahalan MD. Conductance and permeation of monovalent cations through depletion-activated Ca²⁺ channels (ICRAC) in Jurkat T cells. Biophys J 71: 787–794, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B77] 77.Lewis RS. Store-operated calcium channels. Adv Second Messenger Phosphoprotein Res 33: 279–307, 1999. [DOI] [PubMed] [Google Scholar]

[B78] 78.Lewis RS, Cahalan MD. Mitogen-induced oscillations of cytosolic Ca²⁺ and transmembrane Ca²⁺ current in human leukemic T cells. Cell Regul 1: 99–112, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B79] 79.Li Z, Liu L, Deng Y, Ji W, Du W, Xu P, Chen L, Xu T. Graded activation of CRAC channel by binding of different numbers of STIM1 to Orai1 subunits. Cell Res 21: 305–315, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B80] 80.Li Z, Lu J, Xu P, Xie X, Chen L, Xu T. Mapping the interacting domains of STIM1 and Orai1 in Ca²⁺ release-activated Ca²⁺ channel activation. J Biol Chem 282: 29448–29456, 2007. [DOI] [PubMed] [Google Scholar]

[B81] 81.Liao M, Cao E, Julius D, Cheng Y. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504: 107–112, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B83] 83.Liou J, Fivaz M, Inoue T, Meyer T. Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca²⁺ store depletion. Proc Natl Acad Sci USA 104: 9301–9306, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B84] 84.Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T. STIM is a Ca²⁺ sensor essential for Ca²⁺-store-depletion-triggered Ca²⁺ influx. Curr Biol 15: 1235–1241, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B85] 85.Lioudyno MI, Kozak JA, Penna A, Safrina O, Zhang SL, Sen D, Roos J, Stauderman KA, Cahalan MD. Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation. Proc Natl Acad Sci USA 105: 2011–2016, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B86] 86.Lis A, Peinelt C, Beck A, Parvez S, Monteilh-Zoller M, Fleig A, Penner R. CRACM1, CRACM2, and CRACM3 are store-operated Ca²⁺ channels with distinct functional properties. Curr Biol 17: 794–800, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B87] 87.Lis A, Zierler S, Peinelt C, Fleig A, Penner R. A single lysine in the N-terminal region of store-operated channels is critical for STIM1-mediated gating. J Gen Physiol 136: 673–686, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B88] 88.Litjens T, Harland ML, Roberts ML, Barritt GJ, Rychkov GY. Fast Ca²⁺-dependent inactivation of the store-operated Ca²⁺ current (I_SOC) in liver cells: a role for calmodulin. J Physiol 558: 85–97, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B89] 89.Liu Y, Zheng X, Mueller GA, Sobhany M, DeRose EF, Zhang Y, London RE, Birnbaumer L. Crystal structure of calmodulin binding domain of orai1 in complex with Ca²⁺ calmodulin displays a unique binding mode. J Biol Chem 287: 43030–43041, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B90] 90.Luik RM, Wang B, Prakriya M, Wu MM, Lewis RS. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454: 538–542, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B91] 91.Luik RM, Wu MM, Buchanan J, Lewis RS. The elementary unit of store-operated Ca²⁺ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J Cell Biol 174: 815–825, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B92] 92.Ma G, Wei M, He L, Liu C, Wu B, Zhang SL, Jing J, Liang X, Senes A, Tan P, Li S, Sun A, Bi Y, Zhong L, Si H, Shen Y, Li M, Lee MS, Zhou W, Wang J, Wang Y, Zhou Y. Inside-out Ca²⁺ signalling prompted by STIM1 conformational switch. Nat Commun 6: 7826, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B93] 93.Madl J, Weghuber J, Fritsch R, Derler I, Fahrner M, Frischauf I, Lackner B, Romanin C, Schutz GJ. Resting state Orai1 diffuses as homotetramer in the plasma membrane of live mammalian cells. J Biol Chem 285: 41135–41142, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B94] 94.Maleth J, Choi S, Muallem S, Ahuja M. Translocation between PI(4,5)P₂-poor and PI(4,5)P₂-rich microdomains during store depletion determines STIM1 conformation and Orai1 gating. Nat Commun 5: 5843, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B95] 95.Manji SS, Parker NJ, Williams RT, van Stekelenburg L, Pearson RB, Dziadek M, Smith PJ. STIM1: a novel phosphoprotein located at the cell surface. Biochim Biophys Acta 1481: 147–155, 2000. [DOI] [PubMed] [Google Scholar]

[B96] 96.Maruyama Y, Ogura T, Mio K, Kato K, Kaneko T, Kiyonaka S, Mori Y, Sato C. Tetrameric Orai1 is a teardrop-shaped molecule with a long, tapered cytoplasmic domain. J Biol Chem 284: 13676–13685, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B97] 97.Mason JM, Hagemann UB, Arndt KM. Improved stability of the Jun-Fos Activator Protein-1 coiled coil motif: a stopped-flow circular dichroism kinetic analysis. J Biol Chem 282: 23015–23024, 2007. [DOI] [PubMed] [Google Scholar]

[B98] 98.Maus M, Jairaman A, Stathopulos PB, Muik M, Fahrner M, Weidinger C, Benson M, Fuchs S, Ehl S, Romanin C, Ikura M, Prakriya M, Feske S. Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation. Proc Natl Acad Sci USA 112: 6206–6211, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B99] 99.McNally BA, Prakriya M. Permeation, selectivity and gating in store-operated CRAC channels. J Physiol 590: 4179–4191, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B100] 100.McNally BA, Somasundaram A, Jairaman A, Yamashita M, Prakriya M. The C- and N-terminal STIM1 binding sites on Orai1 are required for both trapping and gating CRAC channels. J Physiol 591: 2833–2850, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B101] 101.McNally BA, Somasundaram A, Yamashita M, Prakriya M. Gated regulation of CRAC channel ion selectivity by STIM1. Nature 482: 241–245, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B102] 102.McNally BA, Yamashita M, Engh A, Prakriya M. Structural determinants of ion permeation in CRAC channels. Proc Natl Acad Sci USA 106: 22516–22521, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B103] 103.Mercer JC, Dehaven WI, Smyth JT, Wedel B, Boyles RR, Bird GS, Putney JW Jr. Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J Biol Chem 281: 24979–24990, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B104] 104.Miederer AM, Alansary D, Schwar G, Lee PH, Jung M, Helms V, Niemeyer BA. A STIM2 splice variant negatively regulates store-operated calcium entry. Nat Commun 6: 6899, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B105] 105.Mignen O, Thompson JL, Shuttleworth TJ. Orai1 subunit stoichiometry of the mammalian CRAC channel pore. J Physiol 586: 419–425, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B106] 106.Misceo D, Holmgren A, Louch WE, Holme PA, Mizobuchi M, Morales RJ, De Paula AM, Stray-Pedersen A, Lyle R, Dalhus B, Christensen G, Stormorken H, Tjonnfjord GE, Frengen E. A dominant STIM1 mutation causes Stormorken syndrome. Hum Mutat 35: 556–564, 2014. [DOI] [PubMed] [Google Scholar]

[B107] 107.Morin G, Bruechle NO, Singh AR, Knopp C, Jedraszak G, Elbracht M, Bremond-Gignac D, Hartmann K, Sevestre H, Deutz P, Herent D, Nurnberg P, Romeo B, Konrad K, Mathieu-Dramard M, Oldenburg J, Bourges-Petit E, Shen Y, Zerres K, Ouadid-Ahidouch H, Rochette J. Gain-of-function mutation in STIM1 (P.R304W) is associated with Stormorken syndrome. Hum Mutat 35: 1121–1132, 2014. [DOI] [PubMed] [Google Scholar]

[B108] 108.Muallem S, Fimmel CJ, Pandol SJ, Sachs G. Regulation of free cytosolic Ca²⁺ in the peptic and parietal cells of the rabbit gastric gland. J Biol Chem 261: 2660–2667, 1986. [PubMed] [Google Scholar]

[B109] 109.Muik M, Fahrner M, Derler I, Schindl R, Bergsmann J, Frischauf I, Groschner K, Romanin C. A cytosolic homomerization and a modulatory domain within STIM1 C terminus determine coupling to ORAI1 channels. J Biol Chem 284: 8421–8426, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B110] 110.Muik M, Fahrner M, Schindl R, Stathopulos P, Frischauf I, Derler I, Plenk P, Lackner B, Groschner K, Ikura M, Romanin C. STIM1 couples to ORAI1 via an intramolecular transition into an extended conformation. EMBO J 30: 1678–1689, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B111] 111.Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R, Kahr H, Madl J, Gruber H, Groschner K, Romanin C. Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation. J Biol Chem 283: 8014–8022, 2008. [DOI] [PubMed] [Google Scholar]

[B112] 112.Mullins FM, Park CY, Dolmetsch RE, Lewis RS. STIM1 and calmodulin interact with Orai1 to induce Ca²⁺-dependent inactivation of CRAC channels. Proc Natl Acad Sci USA 106: 15495–15500, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B113] 113.Navarro-Borelly L, Somasundaram A, Yamashita M, Ren D, Miller RJ, Prakriya M. STIM1-Orai1 interactions and Orai1 conformational changes revealed by live-cell FRET microscopy. J Physiol 586: 5383–5401, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B114] 114.Nesin V, Wiley G, Kousi M, Ong EC, Lehmann T, Nicholl DJ, Suri M, Shahrizaila N, Katsanis N, Gaffney PM, Wierenga KJ, Tsiokas L. Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proc Natl Acad Sci USA 111: 4197–4202, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B115] 115.Palty R, Isacoff EY. Cooperative binding of stromal interaction molecule 1 (STIM1) to the N and C termini of calcium release-activated calcium modulator 1 (Orai1). J Biol Chem 291: 334–341, 2016. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B116] 116.Palty R, Raveh A, Kaminsky I, Meller R, Reuveny E. SARAF inactivates the store operated calcium entry machinery to prevent excess calcium refilling. Cell 149: 425–438, 2012. [DOI] [PubMed] [Google Scholar]

[B117] 117.Palty R, Stanley C, Isacoff EY. Critical role for Orai1 C-terminal domain and TM4 in CRAC channel gating. Cell Res 25: 963–980, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B118] 118.Parekh AB. Store-operated channels: mechanisms and function. J Physiol 586: 3033, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B119] 119.Parekh AB. Store-operated CRAC channels: function in health and disease. Nat Rev Drug Discov 9: 399–410, 2010. [DOI] [PubMed] [Google Scholar]

[B120] 120.Parekh AB, Putney JW Jr. Store-operated calcium channels. Physiol Rev 85: 757–810, 2005. [DOI] [PubMed] [Google Scholar]

[B121] 121.Park CY, Hoover PJ, Mullins FM, Bachhawat P, Covington ED, Raunser S, Walz T, Garcia KC, Dolmetsch RE, Lewis RS. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136: 876–890, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B122] 122.Payandeh J, Scheuer T, Zheng N, Catterall WA. The crystal structure of a voltage-gated sodium channel. Nature 475: 353–358, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B123] 123.Peinelt C, Vig M, Koomoa DL, Beck A, Nadler MJ, Koblan-Huberson M, Lis A, Fleig A, Penner R, Kinet JP. Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol 8: 771–773, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B124] 124.Penna A, Demuro A, Yeromin AV, Zhang SL, Safrina O, Parker I, Cahalan MD. The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers. Nature 456: 116–120, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B125] 125.Penner R, Matthews G, Neher E. Regulation of calcium influx by second messengers in rat mast cells. Nature 334: 499–504, 1988. [DOI] [PubMed] [Google Scholar]

[B126] 126.Pozo-Guisado E, Campbell DG, Deak M, Alvarez-Barrientos A, Morrice NA, Alvarez IS, Alessi DR, Martin-Romero FJ. Phosphorylation of STIM1 at ERK1/2 target sites modulates store-operated calcium entry. J Cell Sci 123: 3084–3093, 2010. [DOI] [PubMed] [Google Scholar]

[B127] 127.Pozo-Guisado E, Casas-Rua V, Tomas-Martin P, Lopez-Guerrero AM, Alvarez-Barrientos A, Martin-Romero FJ. Phosphorylation of STIM1 at ERK1/2 target sites regulates interaction with the microtubule plus-end binding protein EB1. J Cell Sci 126: 3170–3180, 2013. [DOI] [PubMed] [Google Scholar]

[B128] 128.Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG. Orai1 is an essential pore subunit of the CRAC channel. Nature 443: 230–233, 2006. [DOI] [PubMed] [Google Scholar]

[B129] 129.Prakriya M, Lewis RS. CRAC channels: activation, permeation, and the search for a molecular identity. Cell Calcium 33: 311–321, 2003. [DOI] [PubMed] [Google Scholar]

[B130] 130.Prakriya M, Lewis RS. Regulation of CRAC channel activity by recruitment of silent channels to a high open-probability gating mode. J Gen Physiol 128: 373–386, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B131] 131.Prakriya M, Lewis RS. Separation and characterization of currents through store-operated CRAC channels and Mg²⁺-inhibited cation (MIC) channels. J Gen Physiol 119: 487–507, 2002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B132] 132.Prakriya M, Lewis RS. Store-operated calcium channels. Physiol Rev 95: 1383–1436, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B133] 133.Putney JW. Pharmacology of store-operated calcium channels. Mol Interv 10: 209–218, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B134] 134.Putney JW., Jr A model for receptor-regulated calcium entry. Cell Calcium 7: 1–12, 1986. [DOI] [PubMed] [Google Scholar]

[B135] 135.Quintana A, Rajanikanth V, Farber-Katz S, Gudlur A, Zhang C, Jing J, Zhou Y, Rao A, Hogan PG. TMEM110 regulates the maintenance and remodeling of mammalian ER-plasma membrane junctions competent for STIM-ORAI signaling. Proc Natl Acad Sci USA 112: E7083–E7092, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B136] 136.Rana A, Yen M, Sadaghiani AM, Malmersjo S, Park CY, Dolmetsch RE, Lewis RS. Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels. J Cell Biol 209: 653–669, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B137] 137.Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA. STIM1, an essential and conserved component of store-operated Ca²⁺ channel function. J Cell Biol 169: 435–445, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B138] 138.Rothberg BS, Wang Y, Gill DL. Orai channel pore properties and gating by STIM: implications from the Orai crystal structure. Sci Signal 6: pe9, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B139] 139.Salido GM, Sage SO, Rosado JA. Biochemical and functional properties of the store-operated Ca²⁺ channels. Cell Signal 21: 457–461, 2009. [DOI] [PubMed] [Google Scholar]

[B140] 140.Sather WA, McCleskey EW. Permeation and selectivity in calcium channels. Annu Rev Physiol 65: 133–159, 2003. [DOI] [PubMed] [Google Scholar]

[B141] 141.Sauc S, Bulla M, Nunes P, Orci L, Marchetti A, Antigny F, Bernheim L, Cosson P, Frieden M, Demaurex N. STIM1L traps and gates Orai1 channels without remodeling the cortical ER. J Cell Sci 128: 1568–1579, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B142] 142.Schindl R, Frischauf I, Bergsmann J, Muik M, Derler I, Lackner B, Groschner K, Romanin C. Plasticity in Ca²⁺ selectivity of Orai1/Orai3 heteromeric channel. Proc Natl Acad Sci USA 106: 19623–19628, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B143] 143.Schindl R, Muik M, Fahrner M, Derler I, Fritsch R, Bergsmann J, Romanin C. Recent progress on STIM1 domains controlling Orai activation. Cell Calcium 46: 227–232, 2009. [DOI] [PubMed] [Google Scholar]

[B144] 144.Schulz I, Schnefel S, Banfic H, Eckhardt L. Ca²⁺ signalling in exocrine glands in comparison to that in vascular smooth muscle cells. Ann NY Acad Sci 488: 240–251, 1986. [DOI] [PubMed] [Google Scholar]

[B145] 145.Scrimgeour N, Litjens T, Ma L, Barritt GJ, Rychkov GY. Properties of Orai1 mediated store-operated current depend on the expression levels of STIM1 and Orai1 proteins. J Physiol 587: 2903–2918, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B146] 146.Scrimgeour NR, Wilson DP, Barritt GJ, Rychkov GY. Structural and stoichiometric determinants of Ca²⁺ release-activated Ca²⁺ (CRAC) channel Ca²⁺-dependent inactivation. Biochim Biophys Acta 1838: 1281–1287, 2014. [DOI] [PubMed] [Google Scholar]

[B147] 147.Sharma S, Quintana A, Findlay GM, Mettlen M, Baust B, Jain M, Nilsson R, Rao A, Hogan PG. An siRNA screen for NFAT activation identifies septins as coordinators of store-operated Ca²⁺ entry. Nature 499: 238–242, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B148] 148.Shuttleworth TJ. Orai3—the “exceptional” Orai? J Physiol 590: 241–257, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B149] 149.Smyth JT, Dehaven WI, Bird GS, Putney JW Jr. Ca²⁺-store-dependent and -independent reversal of Stim1 localization and function. J Cell Sci 121: 762–772, 2008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B150] 150.Soboloff J, Rothberg BS, Madesh M, Gill DL. STIM proteins: dynamic calcium signal transducers. Nat Rev Mol Cell Biol 13: 549–565, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B151] 151.Soboloff J, Spassova MA, Hewavitharana T, He LP, Xu W, Johnstone LS, Dziadek MA, Gill DL. STIM2 is an inhibitor of STIM1-mediated store-operated Ca²⁺ entry. Curr Biol 16: 1465–1470, 2006. [DOI] [PubMed] [Google Scholar]

[B152] 152.Soboloff J, Spassova MA, Tang XD, Hewavitharana T, Xu W, Gill DL. Orai1 and STIM reconstitute store-operated calcium channel function. J Biol Chem 281: 20661–20665, 2006. [DOI] [PubMed] [Google Scholar]

[B153] 153.Spassova MA, Soboloff J, He LP, Xu W, Dziadek MA, Gill DL. STIM1 has a plasma membrane role in the activation of store-operated Ca²⁺ channels. Proc Natl Acad Sci USA 103: 4040–4045, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B154] 154.Srikanth S, Jew M, Kim KD, Yee MK, Abramson J, Gwack Y. Junctate is a Ca²⁺-sensing structural component of Orai1 and stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci USA 109: 8682–8687, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B155] 155.Srikanth S, Jung HJ, Kim KD, Souda P, Whitelegge J, Gwack Y. A novel EF-hand protein, CRACR2A, is a cytosolic Ca²⁺ sensor that stabilizes CRAC channels in T cells. Nat Cell Biol 12: 436–446, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B156] 156.Srikanth S, Jung HJ, Ribalet B, Gwack Y. The intracellular loop of Orai1 plays a central role in fast inactivation of Ca²⁺ release-activated Ca²⁺ channels. J Biol Chem 285: 5066–5075. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B157] 157.Srikanth S, Yee MK, Gwack Y, Ribalet B. The third transmembrane segment of orai1 protein modulates Ca²⁺ release-activated Ca²⁺ (CRAC) channel gating and permeation properties. J Biol Chem 286: 35318–35328, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B158] 158.Stathopulos PB, Ikura M. Partial unfolding and oligomerization of stromal interaction molecules as an initiation mechanism of store operated calcium entry. Biochem Cell Biol 88: 175–183, 2010. [DOI] [PubMed] [Google Scholar]

[B159] 159.Stathopulos PB, Ikura M. Structural aspects of calcium-release activated calcium channel function. Channels (Austin) 7: 344–353, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B160] 160.Stathopulos PB, Li GY, Plevin MJ, Ames JB, Ikura M. Stored Ca²⁺ depletion-induced oligomerization of stromal interaction molecule 1 (STIM1) via the EF-SAM region: an initiation mechanism for capacitive Ca²⁺ entry. J Biol Chem 281: 35855–35862, 2006. [DOI] [PubMed] [Google Scholar]

[B161] 161.Stathopulos PB, Schindl R, Fahrner M, Zheng L, Gasmi-Seabrook GM, Muik M, Romanin C, Ikura M. STIM1/Orai1 coiled-coil interplay in the regulation of store-operated calcium entry. Nat Commun 4: 2963, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B162] 162.Stathopulos PB, Zheng L, Li GY, Plevin MJ, Ikura M. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell 135: 110–122, 2008. [DOI] [PubMed] [Google Scholar]

[B163] 163.Streb H, Irvine RF, Berridge MJ, Schulz I. Release of Ca²⁺ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature 306: 67–69, 1983. [DOI] [PubMed] [Google Scholar]

[B164] 164.Su Z, Shoemaker RL, Marchase RB, Blalock JE. Ca²⁺ modulation of Ca²⁺ release-activated Ca²⁺ channels is responsible for the inactivation of its monovalent cation current. Biophys J 86: 805–814, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B165] 165.Tamura N, Draviam VM. Microtubule plus-ends within a mitotic cell are “moving platforms” with anchoring, signalling and force-coupling roles. Open Biol 2: 120132, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B166] 166.Tirado-Lee L, Yamashita M, Prakriya M. Conformational changes in the Orai1 C-terminus evoked by STIM1 binding. PLoS One 10: e0128622, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B167] 167.Treves S, Franzini-Armstrong C, Moccagatta L, Arnoult C, Grasso C, Schrum A, Ducreux S, Zhu MX, Mikoshiba K, Girard T, Smida-Rezgui S, Ronjat M, Zorzato F. Junctate is a key element in calcium entry induced by activation of InsP₃ receptors and/or calcium store depletion. J Cell Biol 166: 537–548, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B168] 168.Treves S, Vukcevic M, Griesser J, Armstrong CF, Zhu MX, Zorzato F. Agonist-activated Ca²⁺ influx occurs at stable plasma membrane and endoplasmic reticulum junctions. J Cell Sci 123: 4170–4181, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B169] 169.Vig M, Beck A, Billingsley JM, Lis A, Parvez S, Peinelt C, Koomoa DL, Soboloff J, Gill DL, Fleig A, Kinet JP, Penner R. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr Biol 16: 2073–2079, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B170] 170.Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP. CRACM1 is a plasma membrane protein essential for store-operated Ca²⁺ entry. Science 312: 1220–1223, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B172] 172.Walsh CM, Chvanov M, Haynes LP, Petersen OH, Tepikin AV, Burgoyne RD. Role of phosphoinositides in STIM1 dynamics and store-operated calcium entry. Biochem J 425: 159–168, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B173] 173.Wang X, Wang Y, Zhou Y, Hendron E, Mancarella S, Andrake MD, Rothberg BS, Soboloff J, Gill DL. Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site. Nat Commun 5: 3183, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B174] 174.Watanabe T, Noritake J, Kakeno M, Matsui T, Harada T, Wang S, Itoh N, Sato K, Matsuzawa K, Iwamatsu A, Galjart N, Kaibuchi K. Phosphorylation of CLASP2 by GSK-3beta regulates its interaction with IQGAP1, EB1 and microtubules. J Cell Sci 122: 2969–2979, 2009. [DOI] [PubMed] [Google Scholar]

[B175] 175.Webster SM, Del Camino D, Dekker JP, Yellen G. Intracellular gate opening in Shaker K⁺ channels defined by high-affinity metal bridges. Nature 428: 864–868, 2004. [DOI] [PubMed] [Google Scholar]

[B176] 176.Williams RT, Senior PV, Van Stekelenburg L, Layton JE, Smith PJ, Dziadek MA. Stromal interaction molecule 1 (STIM1), a transmembrane protein with growth suppressor activity, contains an extracellular SAM domain modified by N-linked glycosylation. Biochim Biophys Acta 1596: 131–137, 2002. [DOI] [PubMed] [Google Scholar]

[B177] 177.Wissenbach U, Philipp SE, Gross SA, Cavalie A, Flockerzi V. Primary structure, chromosomal localization and expression in immune cells of the murine ORAI and STIM genes. Cell Calcium 42: 439–446, 2007. [DOI] [PubMed] [Google Scholar]

[B178] 178.Wu MM, Buchanan J, Luik RM, Lewis RS. Ca²⁺ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J Cell Biol 174: 803–813, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B179] 179.Yamashita M, Navarro-Borelly L, McNally BA, Prakriya M. Orai1 mutations alter ion permeation and Ca²⁺-dependent fast inactivation of CRAC channels: evidence for coupling of permeation and gating. J Gen Physiol 130: 525–540, 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B180] 180.Yang X, Jin H, Cai X, Li S, Shen Y. Structural and mechanistic insights into the activation of Stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci USA 109: 5657–5662, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B181] 181.Yeromin AV, Zhang SL, Jiang W, Yu Y, Safrina O, Cahalan MD. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443: 226–229, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B182] 182.Yu J, Zhang H, Zhang M, Deng Y, Wang H, Lu J, Xu T, Xu P. An aromatic amino acid in the coiled-coil 1 domain plays a crucial role in the auto-inhibitory mechanism of STIM1. Biochem J 454: 401–409, 2013. [DOI] [PubMed] [Google Scholar]

[B183] 183.Yuan JP, Zeng W, Dorwart MR, Choi YJ, Worley PF, Muallem S. SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat Cell Biol 11: 337–343, 2009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B184] 184.Zhang SL, Yeromin AV, Hu J, Amcheslavsky A, Zheng H, Cahalan MD. Mutations in Orai1 transmembrane segment 1 cause STIM1-independent activation of Orai1 channels at glycine 98 and channel closure at arginine 91. Proc Natl Acad Sci USA 108: 17838–17843, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B185] 185.Zhang SL, Yeromin AV, Zhang XH, Yu Y, Safrina O, Penna A, Roos J, Stauderman KA, Cahalan MD. Genome-wide RNAi screen of Ca²⁺ influx identifies genes that regulate Ca²⁺ release-activated Ca²⁺ channel activity. Proc Natl Acad Sci USA 103: 9357–9362, 2006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B186] 186.Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD. STIM1 is a Ca²⁺ sensor that activates CRAC channels and migrates from the Ca²⁺ store to the plasma membrane. Nature 437: 902–905, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B187] 187.Zhang X, Zhang W, Gonzalez-Cobos JC, Jardin I, Romanin C, Matrougui K, Trebak M. Complex role of STIM1 in the activation of store-independent Orai1/3 channels. J Gen Physiol 143: 345–359, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B188] 188.Zhao Y, Yarov-Yarovoy V, Scheuer T, Catterall WA. A gating hinge in Na⁺ channels; a molecular switch for electrical signaling. Neuron 41: 859–865, 2004. [DOI] [PubMed] [Google Scholar]

[B189] 189.Zheng H, Zhou MH, Hu C, Kuo E, Peng X, Hu J, Kuo L, Zhang SL. Differential roles of the C and N termini of Orai1 protein in interacting with stromal interaction molecule 1 (STIM1) for Ca²⁺ release-activated Ca²⁺ (CRAC) channel activation. J Biol Chem 288: 11263–11272, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B190] 190.Zheng L, Stathopulos PB, Schindl R, Li GY, Romanin C, Ikura M. Auto-inhibitory role of the EF-SAM domain of STIM proteins in store-operated calcium entry. Proc Natl Acad Sci USA 108: 1337–1342, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B191] 191.Zhou Y, Meraner P, Kwon HT, Machnes D, Oh-hora M, Zimmer J, Huang Y, Stura A, Rao A, Hogan PG. STIM1 gates the store-operated calcium channel ORAI1 in vitro. Nat Struct Mol Biol 17: 112–116, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B192] 192.Zhou Y, Ramachandran S, Oh-Hora M, Rao A, Hogan PG. Pore architecture of the ORAI1 store-operated calcium channel. Proc Natl Acad Sci USA 107: 4896–4901, 2010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B193] 193.Zhou Y, Srinivasan P, Razavi S, Seymour S, Meraner P, Gudlur A, Stathopulos PB, Ikura M, Rao A, Hogan PG. Initial activation of STIM1, the regulator of store-operated calcium entry. Nat Struct Mol Biol 20: 973–981, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B194] 194.Zhou Y, Wang X, Wang X, Loktionova NA, Cai X, Nwokonko RM, Vrana E, Wang Y, Rothberg BS, Gill DL. STIM1 dimers undergo unimolecular coupling to activate Orai1 channels. Nat Commun 6: 8395, 2015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B195] 195.Zumbrunn J, Kinoshita K, Hyman AA, Nathke IS. Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3 beta phosphorylation. Curr Biol 11: 44–49, 2001. [DOI] [PubMed] [Google Scholar]

[B196] 196.Zweifach A, Lewis RS. Mitogen-regulated Ca²⁺ current of T lymphocytes is activated by depletion of intracellular Ca²⁺ stores. Proc Natl Acad Sci USA 90: 6295–6299, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]

[B197] 197.Zweifach A, Lewis RS. Rapid inactivation of depletion-activated calcium current (I_CRAC) due to local calcium feedback. J Gen Physiol 105: 209–226, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Molecular mechanisms of STIM/Orai communication

Isabella Derler

Isaac Jardin

Christoph Romanin

Abstract

STIM and Orai Proteins

STIM proteins.

Fig. 1.

Orai proteins.

Fig. 2.

Detailed Presentation of Steps Within STIM1/Orai Signaling Cascade

STIM1 in the resting state.

Activation of STIM1 via Signal Transduction of STIM1 NH₂ Terminus to Its COOH Terminus

Fig. 3.

Coupling of STIM1 to Orai1

STIM1 COOH-terminal regions.

Orai1 COOH terminus.

Orai1 NH₂ terminus.

Both Orai1 NH₂ and COOH Termini Together Determine STIM1-Mediated Activation and Gating

Stoichiometry of STIM1/Orai1 Complex Required for Its Activation

Gating of Orai Channels

Permeability of CRAC/Orai channels.

Ion conduction pathway of the Orai pore.

Fig. 4.

TM Regions Surrounding TM1 Further Contribute to Orai Gating

STIM1 Tunes Orai Channel Gating Characteristics

Inactivation of Orai Channels

Perspectives

GRANTS

DISCLOSURES

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENTS

REFERENCES

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Molecular mechanisms of STIM/Orai communication

Isabella Derler

Isaac Jardin

Christoph Romanin

Abstract

STIM and Orai Proteins

STIM proteins.

Fig. 1.

Orai proteins.

Fig. 2.

Detailed Presentation of Steps Within STIM1/Orai Signaling Cascade

STIM1 in the resting state.

Activation of STIM1 via Signal Transduction of STIM1 NH2 Terminus to Its COOH Terminus

Fig. 3.

Coupling of STIM1 to Orai1

STIM1 COOH-terminal regions.

Orai1 COOH terminus.

Orai1 NH2 terminus.

Both Orai1 NH2 and COOH Termini Together Determine STIM1-Mediated Activation and Gating

Stoichiometry of STIM1/Orai1 Complex Required for Its Activation

Gating of Orai Channels

Permeability of CRAC/Orai channels.

Ion conduction pathway of the Orai pore.

Fig. 4.

TM Regions Surrounding TM1 Further Contribute to Orai Gating

STIM1 Tunes Orai Channel Gating Characteristics

Inactivation of Orai Channels

Perspectives

GRANTS

DISCLOSURES

AUTHOR CONTRIBUTIONS

ACKNOWLEDGMENTS

REFERENCES

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases

Activation of STIM1 via Signal Transduction of STIM1 NH₂ Terminus to Its COOH Terminus

Orai1 NH₂ terminus.

Both Orai1 NH₂ and COOH Termini Together Determine STIM1-Mediated Activation and Gating