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Nat Commun. 2015 Jul 17;6:7826. doi: 10.1038/ncomms8826.

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

Author information

1
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA.
2
Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China.
3
1] High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China [2] University of Science and Technology of China, Hefei, Anhui 230036, China.
4
High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China.
5
Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas 76504, USA.
6
Department of Biochemistry, University of Wisconsin Madison, Madison, Wisconsin 53706, USA.
7
College of Life Sciences, Nankai University, Tianjin 300071, China.
8
Key Laboratory of Chemical Biology, School of Pharmacy, Shandong University, Jinan, Shandong 250012, China.
9
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
10
1] Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas 77030, USA [2] Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Temple, Texas 76504, USA.

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.

PMID:
26184105
PMCID:
PMC4509486
DOI:
10.1038/ncomms8826
[Indexed for MEDLINE]
Free PMC Article

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