Structural rearrangements underlying the activation of STIM1 by ER calcium depletion.

Authors

Ruoyi Qiu, Richard S Lewis

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 34. Pages e2602410123. Aug 25, 2026. Epub Aug 18, 2026.

Abstract

In resting cells, STIM1, the dimeric endoplasmic reticulum (ER) Ca²⁺ sensor that controls store-operated Ca²⁺ entry (SOCE), is held in a Ca²⁺-bound inactive state by multiple intramolecular restraints, or brakes. Receptor-evoked release of Ca²⁺ from the ER causes a large conformational change in STIM1 that releases the brakes and exposes the CRAC activation domain (CAD), enabling it to bind and open store-operated Orai1 channels in the plasma membrane. We performed single-molecule Förster resonance energy transfer (smFRET) measurements with purified STIM1 to better understand how Ca²⁺ release from the luminal domain of STIM1 drives the conformational changes in the cytosolic domain that underlie CAD release. We find that Ca²⁺ removal releases the CAD from CC1α1 (the "CC1 clamp") without obligatory formation of the CC1 coiled-coil that has been associated with CAD release in cells. Surprisingly, the CAD rearranges dramatically during release, as the two hairpin protomers that create its characteristic V-shaped structure are spread apart. Locking the two protomers together by cysteine crosslinking prevents CAD release, suggesting that the CAD must rearrange to escape the CC1 clamp. Our data support a model in which ER depletion-induced dimerization of the luminal SAM domains drives the cytosolic domain into multiple intermediate states including a 3-helix bundle of CC1α1/2/3, releasing the CC1 clamp and allowing the CAD to escape through a "fold-out" mechanism. Subsequent formation of the CC1 coiled-coil enables the CAD to revert to its original shape and extends it toward the plasma membrane to activate Orai1.

PMID:
42612005
Bibliographic data and abstract were imported from PubMed on 19 Aug 2026.

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