Calcium sensing by the STIM1 ER-luminal domain

Aparna Gudlur, Ana Eliza Zeraik, Nupura Hirve, V. Rajanikanth, Andrey A. Bobkov, Guolin Ma, Sisi Zheng, Youjun Wang, Yubin Zhou, Elizabeth A. Komives and Patrick G. Hogan ()
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Aparna Gudlur: La Jolla Institute for Allergy & Immunology
Ana Eliza Zeraik: La Jolla Institute for Allergy & Immunology
Nupura Hirve: La Jolla Institute for Allergy & Immunology
V. Rajanikanth: La Jolla Institute for Allergy & Immunology
Andrey A. Bobkov: Sanford Burnham Prebys Medical Discovery Institute
Guolin Ma: College of Medicine, Texas A&M University
Sisi Zheng: Beijing Normal University
Youjun Wang: Beijing Normal University
Yubin Zhou: College of Medicine, Texas A&M University
Elizabeth A. Komives: University of California–San Diego
Patrick G. Hogan: La Jolla Institute for Allergy & Immunology

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06816-8

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