Inside-out Ca(2+) signalling prompted by STIM1 conformational switch.
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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.
author list (cited authors)
Ma, G., Wei, M., He, L., Liu, C., Wu, B. o., Zhang, S. L., ... Zhou, Y.
complete list of authors
Ma, Guolin||Wei, Ming||He, Lian||Liu, Chongxu||Wu, Bo||Zhang, Shenyuan L||Jing, Ji||Liang, Xiaowen||Senes, Alessandro||Tan, Peng||Li, Siwei||Sun, Aomin||Bi, Yunchen||Zhong, Ling||Si, Hongjiang||Shen, Yuequan||Li, Minyong||Lee, Mi-Sun||Zhou, Weibin||Wang, Junfeng||Wang, Youjun||Zhou, Yubin