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Numbers count: How STIM and Orai stoichiometry affect store-operated calcium entry.
Cell Calcium. 2019 05; 79:35-43.CC

Abstract

Substantial progress has been made in the past several years in establishing the stoichiometries of STIM and Orai proteins and understanding their influence on store-operated calcium entry. Depletion of ER Ca2+ triggers STIM1 to accumulate at ER-plasma membrane junctions where it binds and opens Ca2+ release-activated Ca2+ (CRAC) channels. STIM1 is a dimer, and release of Ca2+ from its two luminal domains is reported to promote their association as well as drive formation of higher-order STIM1 oligomers. The CRAC channel, originally thought to be tetrameric, is now considered to be a hexamer of Orai1 subunits based on crystallographic and electrophysiological studies. STIM1 binding activates CRAC channels in a highly nonlinear way, such that all six Orai1 binding sites must be occupied to account for the activation and signature properties of native channels. The structural basis of STIM1 engagement with the channel is currently unclear, with evidence suggesting that STIM1 dimers bind to individual or pairs of Orai1 subunits. This review examines evidence that has led to points of consensus and debate about STIM1 and Orai1 stoichiometries, and explains the importance of STIM-Orai complex stoichiometry for the regulation of store-operated calcium entry.

Authors+Show Affiliations

Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, United States.Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, 94305, United States. Electronic address: rslewis@stanford.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review

Language

eng

PubMed ID

30807904

Citation

Yen, Michelle, and Richard S. Lewis. "Numbers Count: How STIM and Orai Stoichiometry Affect Store-operated Calcium Entry." Cell Calcium, vol. 79, 2019, pp. 35-43.
Yen M, Lewis RS. Numbers count: How STIM and Orai stoichiometry affect store-operated calcium entry. Cell Calcium. 2019;79:35-43.
Yen, M., & Lewis, R. S. (2019). Numbers count: How STIM and Orai stoichiometry affect store-operated calcium entry. Cell Calcium, 79, 35-43. https://doi.org/10.1016/j.ceca.2019.02.002
Yen M, Lewis RS. Numbers Count: How STIM and Orai Stoichiometry Affect Store-operated Calcium Entry. Cell Calcium. 2019;79:35-43. PubMed PMID: 30807904.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Numbers count: How STIM and Orai stoichiometry affect store-operated calcium entry. AU - Yen,Michelle, AU - Lewis,Richard S, Y1 - 2019/02/12/ PY - 2018/11/20/received PY - 2019/02/06/revised PY - 2019/02/06/accepted PY - 2019/2/27/pubmed PY - 2020/7/22/medline PY - 2019/2/27/entrez KW - CRAC channel KW - Concatemer KW - Orai KW - STIM KW - Stoichiometry KW - Store-operated calcium entry SP - 35 EP - 43 JF - Cell calcium JO - Cell Calcium VL - 79 N2 - Substantial progress has been made in the past several years in establishing the stoichiometries of STIM and Orai proteins and understanding their influence on store-operated calcium entry. Depletion of ER Ca2+ triggers STIM1 to accumulate at ER-plasma membrane junctions where it binds and opens Ca2+ release-activated Ca2+ (CRAC) channels. STIM1 is a dimer, and release of Ca2+ from its two luminal domains is reported to promote their association as well as drive formation of higher-order STIM1 oligomers. The CRAC channel, originally thought to be tetrameric, is now considered to be a hexamer of Orai1 subunits based on crystallographic and electrophysiological studies. STIM1 binding activates CRAC channels in a highly nonlinear way, such that all six Orai1 binding sites must be occupied to account for the activation and signature properties of native channels. The structural basis of STIM1 engagement with the channel is currently unclear, with evidence suggesting that STIM1 dimers bind to individual or pairs of Orai1 subunits. This review examines evidence that has led to points of consensus and debate about STIM1 and Orai1 stoichiometries, and explains the importance of STIM-Orai complex stoichiometry for the regulation of store-operated calcium entry. SN - 1532-1991 UR - https://www.unboundmedicine.com/medline/citation/30807904/Numbers_count:_How_STIM_and_Orai_stoichiometry_affect_store_operated_calcium_entry_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0143-4160(18)30203-3 DB - PRIME DP - Unbound Medicine ER -