Numbers count: How STIM and Orai stoichiometry affect store-operated calcium entry |
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| Affiliation: | 1. Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, UK;2. Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, P.O. Box 24144, Doha, Qatar;1. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA;2. School of Biomedical Engineering, Science, and Health Systems, Drexel University, PA, 19104, USA;3. Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA;3. From the Department of Molecular and Cell Biology and;4. Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, California 94720 and;5. the Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720;1. Center for Nanobiology and Structural Biology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Nové Hrady CZ-373 33, Czech Republic;2. Institute for Biophysics, Johannes Kepler University Linz, A-4040 Linz, Austria;3. Gottfried Schatz Research Center, Medical University of Graz, A-8010 Graz, Austria;4. College of Biomedical Sciences, Larkin University, Miami, FL 33169, United States |
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| 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. |
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| Keywords: | Store-operated calcium entry CRAC channel STIM Orai Stoichiometry Concatemer |
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