Structural features of STIM and Orai underlying store-operated calcium entry.
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ABSTRACT:
SUBMITTER: Qiu R
PROVIDER: S-EPMC6462238 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
Publications
Structural features of STIM and Orai underlying store-operated calcium entry.
Qiu Ruoyi R Lewis Richard S RS
Current opinion in cell biology 20190201
Store-operated calcium entry (SOCE) through Orai channels is triggered by receptor-stimulated depletion of Ca<sup>2+</sup> from the ER. Orai1 is unique in terms of its activation mechanism, biophysical properties, and structure, and its precise regulation is essential for human health. Recent studies have begun to reveal the structural basis of the major steps in the SOCE pathway and how the system is reliably suppressed in resting cells but able to respond robustly to ER Ca<sup>2+</sup> depleti ...[more]
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Project description:Substantial progress has been made in the past several years in establishing the stoichiometries of STIM and Orai proteins and understanding their influence on store-operated calcium entry. Depletion of ER Ca2+ triggers STIM1 to accumulate at ER-plasma membrane junctions where it binds and opens Ca2+ release-activated Ca2+ (CRAC) channels. STIM1 is a dimer, and release of Ca2+ from its two luminal domains is reported to promote their association as well as drive formation of higher-order STIM1 oligomers. The CRAC channel, originally thought to be tetrameric, is now considered to be a hexamer of Orai1 subunits based on crystallographic and electrophysiological studies. STIM1 binding activates CRAC channels in a highly nonlinear way, such that all six Orai1 binding sites must be occupied to account for the activation and signature properties of native channels. The structural basis of STIM1 engagement with the channel is currently unclear, with evidence suggesting that STIM1 dimers bind to individual or pairs of Orai1 subunits. This review examines evidence that has led to points of consensus and debate about STIM1 and Orai1 stoichiometries, and explains the importance of STIM-Orai complex stoichiometry for the regulation of store-operated calcium entry.
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