Inside-out Ca(2+) signalling prompted by STIM1 conformational switch. Academic Article uri icon


  • 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.

published proceedings

  • Nat Commun

altmetric score

  • 4.25

author list (cited authors)

  • Ma, G., Wei, M., He, L., Liu, C., Wu, B. o., Zhang, S. L., ... Zhou, Y.

citation count

  • 126

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

publication date

  • January 2015