ArticleThe Journal of general physiology2016
The inactivation domain of STIM1 is functionally coupled with the Orai1 pore to enable Ca2+-dependent inactivation.
Article in The Journal of general physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 49 citations in OpenAlex.
- Mechanistic insights into Orai dynamics during pore opening.Channels (Austin, Tex.) · 2026Review
- STIM-Orai signaling in neurons: integrating calcium dynamics and synaptic plasticity.Cell communication and signaling : CCS · 2026Review
- Article
- Photocrosslinking-induced CRAC channel-like Orai1 activation independent of STIM1.Nature communications · 2023Article
- A pathogenic human Orai1 mutation unmasks STIM1-independent rapid inactivation of Orai1 channels.eLife · 2023Article
- CRAC and SK Channels: Their Molecular Mechanisms Associated with Cancer Cell Development.Cancers · 2022Review
- The roles of transmembrane family proteins in the regulation of store-operated CaCellular and molecular life sciences : CMLS · 2022Review
- A longer isoform of Stim1 is a negative SOCE regulator but increases cAMP-modulated NFAT signaling.EMBO reports · 2022Article
- Highlighting the Multifaceted Role of Orai1 N-Terminal- and Loop Regions for Proper CRAC Channel Functions.Cells · 2022Review
- STIM and Orai Mediated Regulation of Calcium Signaling in Age-Related Diseases.Frontiers in aging · 2022Review
- Bidirectional regulation of calcium release-activated calcium (CRAC) channel by SARAF.The Journal of cell biology · 2021Article
- Regulation of Store-Operated CaCells · 2021Review
- The Orai Pore Opening Mechanism.International journal of molecular sciences · 2021Review
- Cross-Talk Between the Adenylyl Cyclase/cAMP Pathway and CaReviews of physiology, biochemistry and pharmacology · 2021Review
- STIM Proteins: An Ever-Expanding Family.International journal of molecular sciences · 2020Review
- Molecular Choreography and Structure of CaMembranes · 2020Review
- Cryo-EM structure of the calcium release-activated calcium channel Orai in an open conformation.eLife · 2020Article
- The anatomy ofCurrent opinion in physiology · 2020Article
- Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery.International journal of molecular sciences · 2020Review
- Store-Operated Calcium Channels: From Function to Structure and Back Again.Cold Spring Harbor perspectives in biology · 2020Review
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Authors and funding
2 authors at 1 institution in 1 country.
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Abstract
The inactivation domain of STIM1 (ID(STIM): amino acids 470-491) has been described as necessary for Ca(2+)-dependent inactivation (CDI) of Ca(2+) release-activated Ca(2+) (CRAC) channels, but its mechanism of action is unknown. Here we identify acidic residues within IDSTIM that control the extent of CDI and examine functional interactions of ID(STIM) with Orai1 pore residues W76 and Y80. Alanine scanning revealed three IDSTIM residues (D476/D478/D479) that are critical for generating full CDI. Disabling ID(STIM) by a triple alanine substitution for these three residues ("STIM1 3A") or by truncation of the entire domain (STIM1(1-469)) reduced CDI to the same residual level observed for the Orai1 pore mutant W76A (approximately one third of the extent seen with full-length STIM1). Results of noise analysis showed that STIM11-469 and Orai1 W76A mutants do not reduce channel open probability or unitary Ca(2+) conductance, factors that determine local Ca(2+) accumulation, suggesting that they diminish CDI instead by inhibiting the CDI gating mechanism. We tested for functional coupling between ID(STIM) and the Orai1 pore by double-mutant cycle analysis. The effects on CDI of mutations disabling ID(STIM) or W76 were not additive, demonstrating that ID(STIM) and W76 are strongly coupled and act in concert to generate full-strength CDI. Interestingly, disabling ID(STIM) and W76 separately gave opposite results in Orai1 Y80A channels: channels with W76 but lacking ID(STIM) generated approximately two thirds of the WT extent of CDI but those with ID(STIM) but lacking W76 completely failed to inactivate. Together, our results suggest that Y80 alone is sufficient to generate residual CDI, but acts as a barrier to full CDI. Although ID(STIM) is not required as a Ca(2+) sensor for CDI, it acts in concert with W76 to progress beyond the residual inactivated state and enable CRAC channels to reach the full extent of inactivation.
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