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

Rana, Anshul; Yen, Michelle; Sadaghiani, Amir Masoud; Malmersjö, Seth; Park, Chan Young; Dolmetsch, Ricardo; Lewis, Richard S.

doi:10.1083/jcb.201412060

Cited by 99 publications

(79 citation statements)

References 73 publications

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“…Depletion of ER stores and loss of Ca 2ϩ binding to the luminal EF-hand domains of STIM1 and STIM2 triggers rearrangement of the N and C terminus, opening the CC1/CC3 clamp, and exposing either SOAR1 or SOAR2 for gating and activation of ORAI1 channels (2, 4, 6, 37, 38, 40 -42). Accordingly, 2-APB-induced store-independent Ca 2ϩ entry is mediated through proper interaction and gating of SOAR2 with ORAI1 channels as the dominantnegative splice variant STIM2.1, containing an 8 amino acid insertion within SOAR2 (43,44), demonstrated no increase in cytosolic Ca 2ϩ concentrations in response to 10 M 2-APB ( Fig. 6, A and B).…”

Section: Flexibility Of the Stim2 C Terminus Is Critical To 2-apb Selmentioning

confidence: 93%

Cross-talk between N-terminal and C-terminal domains in stromal interaction molecule 2 (STIM2) determines enhanced STIM2 sensitivity

Emrich

Yoast

Xin

et al. 2019

Journal of Biological Chemistry

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Edited by Roger J. Colbran Store-operated Ca 2؉ entry (SOCE) is a ubiquitous pathway for Ca 2؉ influx across the plasma membrane (PM). SOCE is mediated by the endoplasmic reticulum (ER)-associated Ca 2؉-sensing proteins stromal interaction molecule 1 (STIM1) and STIM2, which transition into an active conformation in response to ER Ca 2؉ store depletion, thereby interacting with and gating PM-associated ORAI1 channels. Although structurally homologous, STIM1 and STIM2 generate distinct Ca 2؉ signatures in response to varying strengths of agonist stimulation. The physiological functions of these Ca 2؉ signatures, particularly under native conditions, remain unclear. To investigate the structural properties distinguishing STIM1 and STIM2 activation of ORAI1 channels under native conditions, here we used CRISPR/Cas9 to generate STIM1 ؊/؊ , STIM2 ؊/؊ , and STIM1/2 ؊/؊ knockouts in HEK293 and colorectal HCT116 cells. We show that depending on cell type, STIM2 can significantly sustain SOCE in response to maximal store depletion. Utilizing the SOCE modifier 2-aminoethoxydiphenyl borate (2-APB), we demonstrate that 2-APB-activated store-independent Ca 2؉ entry is mediated exclusively by endogenous STIM2. Using variants that either stabilize or disrupt intramolecular interactions of STIM C termini, we show that the increased flexibility of the STIM2 C terminus contributes to its selective store-independent activation by 2-APB. However, STIM1 variants with enhanced flexibility in the C terminus failed to supportitsstore-independentactivation.STIM1/STIM2chimericconstructs indicated that coordination between N-terminal sensitivity and C-terminal flexibility is required for specific store-independent STIM2 activation. Our results clarify the structural determinants underlying activation of specific STIM isoforms, insights that are potentially useful for isoform-selective drug targeting.

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Section: Flexibility Of the Stim2 C Terminus Is Critical To 2-apb Selmentioning

confidence: 93%

Cross-talk between N-terminal and C-terminal domains in stromal interaction molecule 2 (STIM2) determines enhanced STIM2 sensitivity

Emrich

Yoast

Xin

et al. 2019

Journal of Biological Chemistry

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“…STIM2, the second member of the vertebrate STIM protein family, is exclusively present in the ER membrane [44], shows 61% amino acid homology and similar domain architecture to STIM1 [45], but presents a lower Ca 2+ binding affinity [46]. The variety of STIM proteins is further enhanced by the existence of diverse splice variants, namely STIM1L [47] and three STIM2 splice variants, STIM2.1 (also known as STIM2β), STIM2.2 (or STIM2α) and STIM2.3 [48,49]. Of these, STIM2.1 is a positive regulator of Orai1, while STIM2.2 inhibits CRAC currents and the function of STIM2.3 is still unknown.…”

Section: Dissecting the Molecular Mechanisms Of Store-operated Calmentioning

confidence: 99%

Pathophysiological Significance of Store-Operated Calcium Entry in Megakaryocyte Function: Opening New Paths for Understanding the Role of Calcium in Thrombopoiesis

Buduo

Balduini

Moccia

2016

IJMS

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Store-Operated Calcium Entry (SOCE) is a universal calcium (Ca2+) influx mechanism expressed by several different cell types. It is now known that Stromal Interaction Molecule (STIM), the Ca2+ sensor of the intracellular compartments, together with Orai and Transient Receptor Potential Canonical (TRPC), the subunits of Ca2+ permeable channels on the plasma membrane, cooperate in regulating multiple cellular functions as diverse as proliferation, differentiation, migration, gene expression, and many others, depending on the cell type. In particular, a growing body of evidences suggests that a tight control of SOCE expression and function is achieved by megakaryocytes along their route from hematopoietic stem cells to platelet production. This review attempts to provide an overview about the SOCE dynamics in megakaryocyte development, with a focus on most recent findings related to its involvement in physiological and pathological thrombopoiesis.

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“…12 It is of particular interest to note that STIM2b, an alternatively spliced form of STIM2, converts STIM isoforms from an activator to an inhibitor of ORAI1. 13 Our findings provide further evidence that the dysregulation of Ca 21 homeostasis underlies the pathomechanism of TAM.…”

Section: Effects Ofmentioning

confidence: 52%

Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1

Saito

Okuma

Mitsui

et al. 2016

Neuromuscular Disorders

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

Abstract: STIM2β is a novel STIM2 splice isoform that inhibits Orai channels.

Cited by 99 publications

References 73 publications

Cross-talk between N-terminal and C-terminal domains in stromal interaction molecule 2 (STIM2) determines enhanced STIM2 sensitivity

Cross-talk between N-terminal and C-terminal domains in stromal interaction molecule 2 (STIM2) determines enhanced STIM2 sensitivity

Pathophysiological Significance of Store-Operated Calcium Entry in Megakaryocyte Function: Opening New Paths for Understanding the Role of Calcium in Thrombopoiesis

Tubular aggregate myopathy caused by a novel mutation in the cytoplasmic domain of STIM1

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