Calcium sensing by the STIM1 ER-luminal domain

Author(s):Show less -

Gudlur, Aparna ^[1] ; Zeraik, Ana Eliza ^{[2, 1]} ; Hirve, Nupura ^[1] ; Rajanikanth, V. ^{[3, 1]} ; Bobkov, Andrey A. ^[4] ; Ma, Guolin ^[5] ; Zheng, Sisi ^[6] ; Wang, Youjun ^[6] ; Zhou, Yubin ^[5] ; Komives, Elizabeth A. ^[7] ; Hogan, Patrick G. ^{[8, 1, 9]}

Affiliation

^[1] La Jolla Inst Allergy & Immunol, Div Signalling & Gene Express, La Jolla, CA 92037 - USA

^[2] Univ Sao Paulo, Inst Fis Sao Carlos, BR-13563120 Sao Carlos, SP - Brazil

^[3] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 - USA

^[4] Sanford Burnham Prebys Med Discovery Inst, Prot Prod & Anal Facil, La Jolla, CA 92037 - USA

^[5] Texas A&M Univ, Coll Med, Inst Biosci & Technol, Ctr Translat Canc Res, Houston, TX 77030 - USA

^[6] Beijing Normal Univ, Coll Life Sci, Beijing Key Lab Gene Resource & Mol Dev, Beijing 100875 - Peoples R China

^[7] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92037 - USA

^[8] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 - USA

^[9] Univ Calif San Diego, Program Immunol, La Jolla, CA 92037 - USA

• Document type: Journal article
• Source: NATURE COMMUNICATIONS; v. 9, OCT 31 2018.
• Web of Science Citations: 7

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. (AU)

• FAPESP's process: 16/12505-8 - Characterization of the calcium release-activated (CRAC) channel in the human pathogen Schistosoma mansoni through the study of its components STIM and ORAI proteins
• Grantee: Ana Eliza Zeraik
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor