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Nat Commun. 2018 Oct 31;9(1):4536. doi: 10.1038/s41467-018-06816-8.

Calcium sensing by the STIM1 ER-luminal domain.

Author information

1
Division of Signalling and Gene Expression, La Jolla Institute for Allergy & Immunology, La Jolla, CA, 92037, USA.
2
Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos, CEP 13563-120, SP, Brazil.
3
H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, 33612, USA.
4
Protein Production and Analysis Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
5
Center for Translational Cancer Research, Institute of Biosciences & Technology, College of Medicine, Texas A&M University, Houston, TX, 77030, USA.
6
Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing, 100875, China.
7
Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, CA, 92037, USA.
8
Division of Signalling and Gene Expression, La Jolla Institute for Allergy & Immunology, La Jolla, CA, 92037, USA. phogan@lji.org.
9
Program in Immunology, University of California-San Diego, La Jolla, CA, 92037, USA. phogan@lji.org.
10
Moores Cancer Center, University of California-San Diego, La Jolla, CA, 92093, USA. phogan@lji.org.

Abstract

Stromal interaction molecule 1 (STIM1) monitors ER-luminal Ca2+ levels to maintain cellular Ca2+ balance and to support Ca2+ signalling. The prevailing view has been that STIM1 senses reduced ER Ca2+ through dissociation of bound Ca2+ from a single EF-hand site, which triggers a dramatic loss of secondary structure and dimerization of the STIM1 luminal domain. Here we find that the STIM1 luminal domain has 5-6 Ca2+-binding sites, that binding at these sites is energetically coupled to binding at the EF-hand site, and that Ca2+ dissociation controls a switch to a second structured conformation of the luminal domain rather than protein unfolding. Importantly, the other luminal-domain Ca2+-binding sites interact with the EF-hand site to control physiological activation of STIM1 in cells. These findings fundamentally revise our understanding of physiological Ca2+ sensing by STIM1, and highlight molecular mechanisms that govern the Ca2+ threshold for activation and the steep Ca2+ concentration dependence.

PMID:
30382093
PMCID:
PMC6208404
DOI:
10.1038/s41467-018-06816-8
[Indexed for MEDLINE]
Free PMC Article

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