Activation of STIM1-Orai1 Involves an Intramolecular Switching Mechanism

Korzeniowski, Marek; Manjarrés, Isabel M.; Várnai, Péter; Balla, Tamás

doi:10.1126/scisignal.2001122

Cited by 190 publications

(334 citation statements)

References 45 publications

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“…These data suggest that STIM1_R304W requires interaction with ORAI1 for the generation of I CRAC. This is consistent with the observation that p.R304W is not located within the CAD/ SOAR or within the inhibitory helix (residues 310-340) that binds to and obstructs CAD/SOAR in resting conditions (34). Interestingly, R304 was predicted to make direct contacts with E318 and Q314, both located within an inhibitory helix (35), suggesting that R304W may indirectly affect interactions between the inhibitory helix and CAD/SOAR in resting conditions.…”

Section: Resultssupporting

confidence: 75%

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Nesin

Wiley

Kousi

et al. 2014

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

221

345

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Signaling through the store-operated Ca 2+ release-activated Ca 2+ (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca 2+ homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca 2+ sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca 2+ -dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca 2+ entry in the treatment of patients with Stormorken syndrome and related pathologic conditions. human genetics | calcium signaling C a 2+ influx in response to the depletion of intracellular Ca 2+ stores, or store-operated Ca 2+ entry, constitutes one of the major routes of Ca 2+ entry in all animal cells (1). Under physiological conditions, Ca 2+ influx is activated in response to numerous G protein-coupled receptors and receptor tyrosine kinases signaling via inositol-1,4,5-trisphosphate as a second messenger (2). Store-operated Ca 2+ entry is mediated primarily by the Ca 2+ release-activated Ca 2+ (CRAC) channel (3), which consists of the pore-forming subunits ORAI1-3 (or CRAC modulators 1-3) and Ca 2+ sensors, STIM1 and STIM2 (4-7). STIM proteins reside in the membrane of endoplasmic reticulum (ER), whereas ORAI proteins reside in the plasma membrane. STIM1 is a single transmembrane-spanning protein (8-12) that, in resting cells, exists as a dimer that binds Ca 2+ through two EF hand-containing domains located in the ER lumen (13). Depletion of Ca 2+ in the ER induces a series of molecular events in the conformation and localization of STIM1, initiated by the formation of higher-order oligomers, protein unfolding, and accumulation at discrete sites in the cell where the ER membrane is in close proximity to the plasma membrane (11,(13)(14)(15)(16). In these sites, STIM1 binds to the cytosolic C and N termini of ORAI1 (17, 18), resulting in channel activation and generation of a highly Ca 2+ -selective CRAC current, or I CRAC (3,19,20). I CRAC is responsible not only ...

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Section: Resultssupporting

confidence: 75%

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Nesin

Wiley

Kousi

et al. 2014

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

221

345

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“…The CAD fragment forms a tetramer in solution ), whereas the longer STIM1 cytosolic fragments generally appear as dimers (Ji et al 2008;Penna et al 2008;Muik et al 2009;Yuan et al 2009;Zhou et al 2010a) that may need to unfold to expose the CAD and activate Orai1 (Korzeniowski et al 2010;Muik et al 2011). These findings raise the intriguing possibility that on store depletion, STIM1 undergoes a conformational change that results in formation of a tetramer through interactions among multiple CADs (Covington et al 2010), an idea that remains to be tested.…”

Section: Accumulation and Activation Of Crac Channels At Er-pm Junctionsmentioning

confidence: 91%

“…Several complementary studies suggest that oligomerization causes the STIM1 cytoplasmic domain to unfold and unmasks a hidden activation domain. Balla and colleagues first noted that an acidic sequence in the Orai1 carboxyl terminus, thought to interact with a basic region in coiledcoil 2 (CC2) of STIM1 (K384-386) (Calloway et al 2009(Calloway et al , 2010, also resembles a region in CC1 of STIM1 (Korzeniowski et al 2010). They hypothesized that the CC2 basic residues may engage this CC1 acidic domain in the resting state, creating an autoinhibitory clamp when stores are full (Figs.…”

Section: Oligomerization Of Stim Is a Regulatory Switch For Socementioning

confidence: 99%

“…3) (Navarro-Borelly et al 2008;Muik et al 2008;Frischauf et al 2009). The structural basis of the STIM-Orai carboxyl terminal interaction is not known, but may involve the formation of heteromeric STIM-Orai coiled-coils ) or more restricted electrostatic interactions between acidic residues in the Orai1 carboxyl terminus (aa 272 -291) and a basic region in the CC2 domain within CAD (K384 -386) (Calloway et al 2009(Calloway et al , 2010Korzeniowski et al 2010).…”

Section: Accumulation and Activation Of Crac Channels At Er-pm Junctionsmentioning

confidence: 99%

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Store-Operated Calcium Channels: New Perspectives on Mechanism and Function

Lewis¹

2011

Cold Spring Harbor Perspectives in Biology

178

201

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Store-operated calcium channels (SOCs) are a nearly ubiquitous Ca 2þ entry pathway stimulated by numerous cell surface receptors via the reduction of Ca 2þ concentration in the ER. The discovery of STIM proteins as ER Ca 2þ sensors and Orai proteins as structural components of the Ca 2þ release-activated Ca 2þ (CRAC) channel, a prototypic SOC, opened the floodgates for exploring the molecular mechanism of this pathway and its functions. This review focuses on recent advances made possible by the use of STIM and Orai as molecular tools. I will describe our current understanding of the store-operated Ca 2þ entry mechanism and its emerging roles in physiology and disease, areas of uncertainty in which further progress is needed, and recent findings that are opening new directions for research in this rapidly growing field.

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“…In particular, the model predicts that the helical stretch of basic residues (KIKKKR; Fig. 1 H, highlighted in purple) known to play a critical role in binding to Orai1 (Calloway et al, 2009(Calloway et al, , 2010Korzeniowski et al, 2010) is likely to be disrupted in STIM2β, whereas the regions responsible for STIM-STIM dimerization (Yang et al, 2012;Stathopulos et al, 2013) (Brandman et al, 2007). We applied thapsigargin (Tg) to deplete Ca 2+ stores and examine the effects of STIM2α and STIM2β on SOCE in HEK293 cells overexpressing Orai1 (Fig.…”

Section: Stim2β Is a Novel And Widely Expressed Stim2 Splice Isoformmentioning

confidence: 99%

Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels

Rana¹,

Yen²,

Sadaghiani³

et al. 2015

J Gen Physiol

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Activation of STIM1-Orai1 Involves an Intramolecular Switching Mechanism

Cited by 190 publications

References 45 publications

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis

Store-Operated Calcium Channels: New Perspectives on Mechanism and Function

Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels

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