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Molecular basis of allosteric Orai1 channel activation by STIM1
Store‐operated Ca2+ entry through Orai1 channels is a primary mechanism for Ca2+ entry in many cells and mediates numerous cellular effector functions ranging from gene transcription to exocytosis. Orai1 channels are amongst the most Ca2+‐selective channels known and are activated by direct physical...
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Published in: | The Journal of physiology 2020-05, Vol.598 (9), p.1707-1723 |
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Main Authors: | , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | Store‐operated Ca2+ entry through Orai1 channels is a primary mechanism for Ca2+ entry in many cells and mediates numerous cellular effector functions ranging from gene transcription to exocytosis. Orai1 channels are amongst the most Ca2+‐selective channels known and are activated by direct physical interactions with the endoplasmic reticulum Ca2+ sensor stromal interaction molecule 1 (STIM1) in response to store depletion triggered by stimulation of a variety of cell surface G‐protein coupled and tyrosine kinase receptors. Work in the last decade has revealed that the Orai1 gating process is highly cooperative and strongly allosteric, likely driven by a wave of interdependent conformational changes throughout the protein originating in the peripheral C‐terminal ligand binding site and culminating in pore opening. In this review, we survey the structural and molecular features in Orai1 that contribute to channel gating and consider how they give rise to the unique biophysical fingerprint of Orai1 currents.
Activation of store‐operated Orai1 channels. Following the depletion of endoplasmic reticulum (ER) Ca2+ stores, STIM1 binds to Orai1 at ER–plasma membrane junctions. Inset: the channel activation process involves a conformational wave throughout the transmembrane domains of Orai1, starting from the peripheral C‐terminal extensions and propagating towards the central pore. |
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ISSN: | 0022-3751 1469-7793 |
DOI: | 10.1113/JP276550 |