Initial activation of STIM1, the regulator of store-operated calcium entry

Zhou, Yubin; Srinivasan, Prasanna; Razavi, Shiva; Seymour, Sam; Meraner, Paul; Gudlur, Aparna; Stathopulos, Peter B.; Ikura, Mitsuhiko; Rao, Anjana; Hogan, Patrick G.

doi:10.1038/nsmb.2625

Cited by 182 publications

(324 citation statements)

References 60 publications

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“…The C terminus of STIM1 adopts an inactive conformation in cells with filled Ca 2+ stores (9)(10)(11)21) and undergoes a conformational extension upon ER store depletion, allowing STIM1 to bridge the gap between the ER and PM. The molecular mechanisms controlling this transition are incompletely understood but were proposed to involve hydrophobic (10) and electrostatic interactions (9,21,26) between the CC1 and CC2 domains of STIM1-CT.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular mechanisms controlling this transition are incompletely understood but were proposed to involve hydrophobic (10) and electrostatic interactions (9,21,26) between the CC1 and CC2 domains of STIM1-CT. The role of CC1 in maintaining STIM1-CT in a closed, inactive conformation has been demonstrated by in vitro studies (10,11) and is emphasized by recent reports identifying a gain-of-function mutation in CC1 (R304W) as the cause of Stormorken syndrome (27)(28)(29). Our studies of the R429C patient mutation highlight a hitherto unappreciated role for CC3 in addition to CC1 in maintaining the inactive conformation of STIM1, as mutant STIM1-R429C adopts a constitutively open conformation and localizes to ER-PM junctions independently of ER store Ca 2+ content.…”

Section: Discussionmentioning

confidence: 99%

“…We hypothesized that increased E-FRET may be due to constitutive and store-independent low affinity interactions between mutant STIM1-R429C molecules at spatially constrained ER-PM junctions with high STIM1 concentrations. Recruitment of STIM1 to ER-PM junctions is dependent on the binding of the C-terminal polybasic domain of STIM1 (amino acids 675-685) to negatively charged PM phospholipids (11,13). Deletion of the polybasic domain (ΔK) in STIM1-WT had no effect on either baseline E-FRET or the E-FRET increase after store depletion (Fig.…”

Section: R429 Is Required For Store Depletion-induced Homotypic Stim1-ctmentioning

confidence: 92%

“…These events result in a conformational extension of the cytoplasmic C terminus of STIM1 (STIM-CT) (9)(10)(11)(12) and exposure of a polybasic domain at the distal end of STIM1-CT. The polybasic domain interacts with acidic phospholipids in the PM, thereby facilitating recruitment of STIM1 oligomers to ER-PM junctions (9)(10)(11)13) and subsequent binding of ORAI1. The STIM1-CT contains three coiled-coil (CC) domains: CC1 (amino acids 247-336), CC2 (amino acids 345-391), and CC3 (amino acids 408-437) (Fig.…”

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confidence: 99%

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Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation

Maus

Jairaman

Stathopulos

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Store-operated Ca 2+ entry (SOCE) is a universal Ca 2+ influx pathway that is important for the function of many cell types. SOCE occurs upon depletion of endoplasmic reticulum (ER) Ca 2+ stores and relies on a complex molecular interplay between the plasma membrane (PM) Ca 2+ channel ORAI1 and the ER Ca 2+ sensor stromal interaction molecule (STIM) 1. Patients with null mutations in ORAI1 or STIM1 genes present with severe combined immunodeficiency (SCID)-like disease. Here, we describe the molecular mechanisms by which a loss-of-function STIM1 mutation (R429C) in human patients abolishes SOCE. R429 is located in the third coiled-coil (CC3) domain of the cytoplasmic C terminus of STIM1. Mutation of R429 destabilizes the CC3 structure and alters the conformation of the STIM1 C terminus, thereby releasing a polybasic domain that promotes STIM1 recruitment to ER-PM junctions. However, the mutation also impairs cytoplasmic STIM1 oligomerization and abolishes STIM1-ORAI1 interactions. Thus, despite its constitutive localization at ER-PM junctions, mutant STIM1 fails to activate SOCE. Our results demonstrate multifunctional roles of the CC3 domain in regulating intra-and intermolecular STIM1 interactions that control (i) transition of STIM1 from a quiescent to an active conformational state, (ii) cytoplasmic STIM1 oligomerization, and (iii) STIM1-ORAI1 binding required for ORAI1 activation.release-activated Ca 2+ (CRAC) channels in the plasma membrane (PM) that are formed by multimers of ORAI proteins, which constitute the permeation pore of the channel (1-4). The opening of ORAI channels is mediated by stromal interaction molecule (STIM) 1 and STIM2, single pass transmembrane proteins whose N and C termini are located in the endoplasmic reticulum (ER) lumen and cytoplasm, respectively (5, 6). STIM1 and STIM2 are activated after depletion of ER Ca 2+ stores in response to ligation of cell surface receptors that mediate phospholipase C (PLC) activation. The importance of SOCE is emphasized by null and loss-of-function mutations in ORAI1 and STIM1 genes, which cause a disease syndrome called CRAC channelopathy that is characterized by immunodeficiency, autoimmunity, ectodermal dysplasia, and skeletal myopathy (7). SOCE is a highly choreographed process that involves a complex conformational rearrangement of STIM1 proteins, their oligomerization in the ER lumen and in the cytoplasm, and subsequent translocation from the bulk ER to ER-PM junctions (4, 8). There, STIM1 oligomers form puncta and bind ORAI1. SOCE is initiated by dissociation of Ca 2+ from a paired EF-hand (EFh) domain in the ER luminal N terminus of STIM1 after store depletion (Fig. 1A) and association of STIM1 N termini. These events result in a conformational extension of the cytoplasmic

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: R429 Is Required For Store Depletion-induced Homotypic Stim1-ctmentioning

confidence: 92%

mentioning

confidence: 99%

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Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation

Maus

Jairaman

Stathopulos

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The process begins when depletion of calcium from the ER leads to calcium disassociation from the EF hand of STIM1, facilitating dimerization of SAM domains [21]. Dimerization of STIM1 ER luminal domains triggers extensive conformational changes in the cytoplasmic domains that lead to the exposure of CAD [20,[22][23][24][25][26]. CAD binds with low affinity to a site in the Orai1 N terminal (NBD, residues 73-87; Figure 1A) and with higher affinity to a site in the Orai1 C terminal (CBD, residues 267-292; Figure 1A) [14,15,28,29].…”

Section: Introductionmentioning

confidence: 99%

Critical role for Orai1 C-terminal domain and TM4 in CRAC channel gating

2015

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Calcium flux through store-operated calcium entry is a major regulator of intracellular calcium homeostasis and various calcium signaling pathways. Two key components of the store-operated calcium release-activated calcium channel are the Ca 2+-sensing protein stromal interaction molecule 1 (STIM1) and the channel pore-forming protein Orai1. Following calcium depletion from the endoplasmic reticulum, STIM1 undergoes conformational changes that unmask an Orai1-activating domain called CAD. CAD binds to two sites in Orai1, one in the N terminal and one in the C terminal. Most previous studies suggested that gating is initiated by STIM1 binding at the Orai1 N-terminal site, just proximal to the TM1 pore-lining segment, and that binding at the C terminal simply anchors STIM1 within reach of the N terminal. However, a recent study had challenged this view and suggested that the Orai1 C-terminal region is more than a simple STIM1-anchoring site. In this study, we establish that the Orai1 C-terminal domain plays a direct role in gating. We identify a linker region between TM4 and the C-terminal STIM1-binding segment of Orai1 as a key determinant that couples STIM1 binding to gating. We further find that Proline 245 in TM4 of Orai1 is essential for stabilizing the closed state of the channel. Taken together with previous studies, our results suggest a dual-trigger mechanism of Orai1 activation in which binding of STIM1 at the N-and C-terminal domains of Orai1 induces rearrangements in proximal membrane segments to open the channel.

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Caffeine‐Operated Synthetic Modules for Chemogenetic Control of Protein Activities by Life Style

Wang

et al. 2020

Advanced Science

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A genetically encoded caffeine‐operated synthetic module (COSMO) is introduced herein as a robust chemically induced dimerization (CID) system. COSMO enables chemogenetic manipulation of biological processes by caffeine and its metabolites, as well as caffeinated beverages, including coffee, tea, soda, and energy drinks. This CID tool, evolved from an anti‐caffeine nanobody via cell‐based high‐throughput screening, permits caffeine‐inducible gating of calcium channels, tumor killing via necroptosis, growth factors‐independent activation of tyrosine receptor kinase signaling, and enhancement of nanobody‐mediated antigen recognition for the severe acute respiratory distress coronavirus 2 (SARS‐CoV‐2) spike protein. Further rationalized engineering of COSMO leads to 34–217‐fold enhancement in caffeine sensitivity (EC50 = 16.9 nanomolar), which makes it among the most potent CID systems like the FK506 binding protein (FKBP)–FKBP rapamycin binding domain (FRB)–rapamycin complex. Furthermore, bivalent COSMO (biCOMSO) connected with a long linker favors intramolecular dimerization and acts as a versatile precision switch when inserted in host proteins to achieve tailored function. Given the modularity and high transferability of COMSO and biCOSMO, these chemical biology tools are anticipated to greatly accelerate the development of therapeutic cells and biologics that can be switched on and off by caffeinated beverages commonly consumed in the daily life.

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Initial activation of STIM1, the regulator of store-operated calcium entry

Cited by 182 publications

References 60 publications

Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation

Missense mutation in immunodeficient patients shows the multifunctional roles of coiled-coil domain 3 (CC3) in STIM1 activation

Critical role for Orai1 C-terminal domain and TM4 in CRAC channel gating

Caffeine‐Operated Synthetic Modules for Chemogenetic Control of Protein Activities by Life Style

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