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


Journal Article

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.

Full Text

Cited Authors

  • Ma, G; Wei, M; He, L; Liu, C; Wu, B; Zhang, SL; Jing, J; Liang, X; Senes, A; Tan, P; Li, S; Sun, A; Bi, Y; Zhong, L; Si, H; Shen, Y; Li, M; Lee, M-S; Zhou, W; Wang, J; Wang, Y; Zhou, Y

Published Date

  • July 17, 2015

Published In

Volume / Issue

  • 6 /

Start / End Page

  • 7826 -

PubMed ID

  • 26184105

Pubmed Central ID

  • 26184105

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms8826


  • eng