Molecular Biophysics of Orai Store-Operated Ca2+ Channels |
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| Authors: | Anna Amcheslavsky Mona?L. Wood Andriy?V. Yeromin Ian Parker J.?Alfredo Freites Douglas?J. Tobias Michael?D. Cahalan |
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| Affiliation: | 1Department of Physiology and Biophysics, University of California at Irvine, Irvine, California;2Department of Chemistry, University of California at Irvine, Irvine, California;3Department of Neurobiology and Behavior, University of California at Irvine, Irvine, California;4Institute for Immunology, University of California at Irvine, Irvine, California |
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| Abstract: | Upon endoplasmic reticulum Ca2+ store depletion, Orai channels in the plasma membrane are activated directly by endoplasmic reticulum-resident STIM proteins to generate the Ca2+-selective, Ca2+ release-activated Ca2+ (CRAC) current. After the molecular identification of Orai, a plethora of functional and biochemical studies sought to compare Orai homologs, determine their stoichiometry, identify structural domains responsible for the biophysical fingerprint of the CRAC current, identify the physiological functions, and investigate Orai homologs as potential therapeutic targets. Subsequently, the solved crystal structure of Drosophila Orai (dOrai) substantiated many findings from structure-function studies, but also revealed an unexpected hexameric structure. In this review, we explore Orai channels as elucidated by functional and biochemical studies, analyze the dOrai crystal structure and its implications for Orai channel function, and present newly available information from molecular dynamics simulations that shed light on Orai channel gating and permeation. |
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