The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function

Jha, Archana; Ahuja, Malini; Maléth, József; Moreno, Cláudia; Yuan, Joseph P.; Kim, Min Seuk; Muallem, Shmuel

doi:10.1083/jcb.201301148

Cited by 116 publications

(178 citation statements)

References 28 publications

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“…This process leaves a "STIM1-free" but partially active Orai1 P245L that contributes to the measured current and therefore to an apparent reduction of the slow inactivation process. Two other mutants, G98S and L138F, which have also been associated with tubular aggregate myopathy and congenital miosis syndromes [65], share the defect that we identified in P245L of constitutive channel opening [43,53,65]. Although the constitutive conductance of Orai1 P245L may be less pronounced in heterozygous patients than in heterologous overexpression experiments due to formation of mutant and WT heteromultimers, based on results presented here and on previous findings, we propose that STIM1-independent constitutive channel activation of Orai1 channels is likely the common factor that underlies the disease state.…”

Section: How Mutation In the Tm4 Proline Bend Might Induce Myopathymentioning

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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Section: How Mutation In the Tm4 Proline Bend Might Induce Myopathymentioning

confidence: 99%

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

2015

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“…Furthermore, SARAF has been reported to modulate cytosolic and ER Ca 2ϩ concentration (8). The activation of SARAF requires the intraluminal (N-terminal) region, while the interaction with SARAF involves the cytosolic region, which interacts with the C-terminal inhibitory domain of STIM1 (downstream the STIM1 Orai1 activation region (SOAR)) to regulate the STIM1/ Orai1 interaction (9). SARAF is associated with STIM1 under resting conditions and translocates to ER-PM regions in a STIM1-dependent manner (8).…”

mentioning

confidence: 99%

Store-operated Ca2+ Entry-associated Regulatory factor (SARAF) Plays an Important Role in the Regulation of Arachidonate-regulated Ca2+ (ARC) Channels

Albarrán

López

Woodard

et al. 2016

Journal of Biological Chemistry

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The store-operated Ca 2؉ entry-associated regulatory factor (SARAF) has recently been identified as a STIM1 regulatory protein that facilitates slow Ca 2؉ -dependent inactivation of store-operated Ca 2؉ entry (SOCE). Both the store-operated channels and the store-independent arachidonate-regulated Ca 2؉ (ARC) channels are regulated by STIM1. In the present study, we show that, in addition to its location in the endoplasmic reticulum, SARAF is constitutively expressed in the plasma membrane, where it can interact with plasma membrane (PM)-resident ARC forming subunits in the neuroblastoma cell line SH-SY5Y. Using siRNA-based and overexpression approaches we report that SARAF negatively regulates store-independent Ca 2؉ entry via the ARC channels. Arachidonic acid (AA) increases the association of PM-resident SARAF with Orai1. Finally, our results indicate that SARAF modulates the ability of AA to promote cell survival in neuroblastoma cells. In addition to revealing new insight into the biology of ARC channels in neuroblastoma cells, these findings provide evidence for an unprecedented location of SARAF in the plasma membrane.

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“…Deletion of the CTID region has been reported to induce spontaneous clustering of STIM1 and activation of CRAC channels independently of Ca 2C store depletion. 5 Studies performed in Muallems lab revealed that SARAF is associated to STIM1 at rest and Ca 2C store depletion results in a initial dissociation followed by re-interaction of both proteins. 5 Recently, we have reported that maximal dissociation occurs after 30 s of the initiation of store depletion by treatment with TG, and full re-association is achieved 30 s later.…”

Section: Introductionmentioning

confidence: 99%

“…5 Studies performed in Muallems lab revealed that SARAF is associated to STIM1 at rest and Ca 2C store depletion results in a initial dissociation followed by re-interaction of both proteins. 5 Recently, we have reported that maximal dissociation occurs after 30 s of the initiation of store depletion by treatment with TG, and full re-association is achieved 30 s later. 6 In parallel, we have observed a reciprocal interaction of SARAF with Orai1 that might be aimed to enhanced Orai1 channel function as determined in NG115-401L cells lacking a significant expression of STIM1.…”

Section: Introductionmentioning

confidence: 99%

“…4 SARAF is a protein with a single putative transmembrane domain, a N-terminal region that is required for the activation of the protein, and a C-terminal domain that has been shown to be involved in the interaction with the C-terminal inhibitory domain of STIM1 (CTID), downstream the STIM1 Orai1 activation region (SOAR)). 5 Using homology modeling the STIM1 CTID region (amino acids 448-530) was identified, which contains 2 lobes: the STIM1 (448-490) lobe was found to restrict the interaction of SARAF with the SOAR region, while the STIM1 (490-530) lobe direct the SARAF-SOAR interaction. Deletion of the CTID region has been reported to induce spontaneous clustering of STIM1 and activation of CRAC channels independently of Ca 2C store depletion.…”

Section: Introductionmentioning

confidence: 99%

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Role of STIM1 in the surface expression of SARAF

et al. 2016

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The store-operated Ca 2C entry-associated regulatory factor (SARAF), a protein expressed both in the endoplasmic reticulum and the plasma membrane, has been presented as a STIM1-interacting protein with the ability to modulate intracellular Ca 2C homeostasis. SARAF negatively modulates store-operated Ca 2C entry (SOCE) by preventing STIM1 spontaneous activation and regulating STIM1-Orai1 complex formation. In addition, SARAF is a negative regulator of Ca 2C entry through the arachidonate-regulated Ca 2C (ARC) channels. Here we explored the possible role of the surface expression of SARAF on the location of STIM1 in the plasma membrane. In NG115-401L cells, lacking a detectable expression of native STIM1, transfection with pHluorin-STIM1, which is able to translocate to the cell surface, enhances the plasma membrane location of SARAF as compared to cells transfected with YFP-STIM1, lacking the ability to translocate to the cell surface. These findings suggest that the surface location of SARAF is dependent on the expression of STIM1 in the plasma membrane.

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The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function

Abstract: Two distinct lobes in the C-terminal inhibitory domain in STIM1 determine access of the inhibitor SARAF to the activating SOAR domain to regulate the slow Ca2+-dependent inactivation of Orai1.

Cited by 116 publications

References 28 publications

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

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

Store-operated Ca2+ Entry-associated Regulatory factor (SARAF) Plays an Important Role in the Regulation of Arachidonate-regulated Ca2+ (ARC) Channels

Role of STIM1 in the surface expression of SARAF

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