Multiple weak brakes act in concert to control STIM1 and store- operated calcium entry

• 成果类型: Article
• 署名作者: Qiu, Ruoyi; Lewis, Richard S.
• 署名单位: Stanford Medicine; Stanford University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2518622122
• 发表日期: 2025-12-16
• 页码: e2518622122
• 关键词: calcium signaling; single-molecule FRET; store-operated calcium entry; stim1; crac channels; coiled-coil; mechanistic insights; activation; domain; oligomerization; orai1; initiation; regulator; depletion

摘要

Store- operated Ca2+ entry is a key signaling pathway controlled by the interaction of To avoid generating pathological effects, STIM1 must remain mostly inactive under content. It is not well understood how these conflicting requirements are met. Here we combine single- molecule FRET measurements of full- length dimeric STIM1 in lipid membranes with an AlphaFold2 structural model to describe the structure and regulation of the resting state. We show that STIM1 activity is controlled by the comluminal domain acts as a steric restraint to inhibit spontaneous activity. In the cytosolic CC3 of the CRAC activation domain (CAD) positions the apex of CAD next to the ER membrane, where electrostatic lipid-protein interactions further stabilize the inactive conformation. A fourth brake is created by hydrophobic and electrostatic interactions of the two CC1 alpha 2/3 domains attached to the base of CAD. Disruption of any one of these brakes triggers spontaneous STIM1 activation, showing that the concerted action of these relatively weak restraints serves to minimize spontaneous activity in resting in store content.