ArticleCell research2015
Critical role for Orai1 C-terminal domain and TM4 in CRAC channel gating.
Article in Cell research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 83 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
- Unraveling cooperative and competitive interactions within protein triplets in the human interactome.Scientific reports · 2025Article
- ORAI CaBiomolecules · 2024Review
- 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
- Photopharmacological modulation of native CRAC channels using azoboronate photoswitches.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The Role of Lipids in CRAC Channel Function.Biomolecules · 2022Review
- Orai1 Boosts SK3 Channel Activation.Cancers · 2021Article
- Bidirectional regulation of calcium release-activated calcium (CRAC) channel by SARAF.The Journal of cell biology · 2021Article
- Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation.Molecular cell · 2021Article
- Structural Insights into CaCells · 2021Review
- Defects in the STIM1 SOARα2 domain affect multiple steps in the CRAC channel activation cascade.Cellular and molecular life sciences : CMLS · 2021Article
- Isoform-Specific Properties of Orai Homologues in Activation, Downstream Signaling, Physiology and Pathophysiology.International journal of molecular sciences · 2021Review
- Regulation of Store-Operated CaCells · 2021Review
- Endoplasmic Reticulum-Plasma Membrane Contact Sites as an Organizing Principle for Compartmentalized Calcium and cAMP Signaling.International journal of molecular sciences · 2021Review
- The Orai Pore Opening Mechanism.International journal of molecular sciences · 2021Review
- Store-Operated Calcium Entry in the Cardiovascular System.Advances in experimental medicine and biology · 2021Review
- Transmembrane Domain 3 (TM3) Governs Orai1 and Orai3 Pore Opening in an Isoform-Specific Manner.Frontiers in cell and developmental biology · 2021Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.