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Inside-out Ca(2+) signalling prompted by STIM1 conformational switch.

Nature communications (2015-07-18)
Guolin Ma, Ming Wei, Lian He, Chongxu Liu, Bo Wu, Shenyuan L Zhang, Ji Jing, Xiaowen Liang, Alessandro Senes, Peng Tan, Siwei Li, Aomin Sun, Yunchen Bi, Ling Zhong, Hongjiang Si, Yuequan Shen, Minyong Li, Mi-Sun Lee, Weibin Zhou, Junfeng Wang, Youjun Wang, Yubin Zhou
ABSTRACT

Store-operated Ca(2+) entry mediated by STIM1 and ORAI1 constitutes one of the major Ca(2+) entry routes in mammalian cells. The molecular choreography of STIM1-ORAI1 coupling is initiated by endoplasmic reticulum (ER) Ca(2+) store depletion with subsequent oligomerization of the STIM1 ER-luminal domain, followed by its redistribution towards the plasma membrane to gate ORAI1 channels. The mechanistic underpinnings of this inside-out Ca(2+) signalling were largely undefined. By taking advantage of a unique gain-of-function mutation within the STIM1 transmembrane domain (STIM1-TM), here we show that local rearrangement, rather than alteration in the oligomeric state of STIM1-TM, prompts conformational changes in the cytosolic juxtamembrane coiled-coil region. Importantly, we further identify critical residues within the cytoplasmic domain of STIM1 (STIM1-CT) that entail autoinhibition. On the basis of these findings, we propose a model in which STIM1-TM reorganization switches STIM1-CT into an extended conformation, thereby projecting the ORAI-activating domain to gate ORAI1 channels.

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