分子的决定基因活化中存储操作的Ca2 +条目

Title:Molecular Determinants for STIM1 Activation During Store- Operated Ca2+ Entry

Volume: 17 Issue: 1

关键词: 钙信号，Orai1、STIM1，蛋白质-蛋白质相互作用，钙进入，钙释放激活的钙通道，FRET，成像。

摘要: Background: STIM/ORAI-mediated store-operated Ca2+ entry (SOCE) mediates a myriad of Ca2+-dependent cellular activities in mammals. Genetic defects in STIM1/ORAI1 lead to devastating severe combined immunodeficiency; whereas gain-offunction mutations in STIM1/ORAI1 are intimately associated with tubular aggregate myopathy. At molecular level, a decrease in the Ca2+ concentrations within the lumen of endoplasmic reticulum (ER) initiates multimerization of the STIM1 luminal domain to switch on the STIM1 cytoplasmic domain to engage and gate ORAI channels, thereby leading to the ultimate Ca2+ influx from the extracellular space into the cytosol. Despite tremendous progress made in dissecting functional STIM1-ORAI1 coupling, the activation mechanism of SOCE remains to be fully characterized.

Objective and Methods: Building upon a robust fluorescence resonance energy transfer assay designed to monitor STIM1 intramolecular autoinhibition, we aimed to systematically dissect the molecular determinants required for the activation and oligomerization of STIM1.

Results: Here we showed that truncation of the STIM1 luminal domain predisposes STIM1 to adopt a more active conformation. Replacement of the single transmembrane (TM) domain of STIM1 by a more rigid dimerized TM domain of glycophorin A abolished STIM1 activation. But this adverse effect could be partially reversed by disrupting the TM dimerization interface. Moreover, our study revealed regions that are important for the optimal assembly of hetero-oligomers composed of full-length STIM1 with its minimal STIM1-ORAI activating region, SOAR.

Conclusions: Our study clarifies the roles of major STIM1 functional domains in maintaining a quiescent configuration of STIM1 to prevent preactivation of SOCE.

Cite this article as:

Molecular Determinants for STIM1 Activation During Store- Operated Ca2+ Entry, Current Molecular Medicine 2017; 17 (1) . https://dx.doi.org/10.2174/1566524017666170220103731

DOI https://dx.doi.org/10.2174/1566524017666170220103731	Print ISSN 1566-5240
Publisher Name Bentham Science Publisher	Online ISSN 1875-5666