1. Selenoprotein N is an endoplasmic reticulum calcium sensor that links luminal calcium levels to a redox activity.
- Author
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Chernorudskiy A, Varone E, Colombo SF, Fumagalli S, Cagnotto A, Cattaneo A, Briens M, Baltzinger M, Kuhn L, Bachi A, Berardi A, Salmona M, Musco G, Borgese N, Lescure A, and Zito E
- Subjects
- HeLa Cells, Humans, Intracellular Calcium-Sensing Proteins genetics, Muscle Proteins genetics, Oxidation-Reduction, Selenoproteins genetics, Calcium metabolism, Endoplasmic Reticulum metabolism, Intracellular Calcium-Sensing Proteins metabolism, Muscle Proteins metabolism, Selenoproteins metabolism
- Abstract
The endoplasmic reticulum (ER) is the reservoir for calcium in cells. Luminal calcium levels are determined by calcium-sensing proteins that trigger calcium dynamics in response to calcium fluctuations. Here we report that Selenoprotein N (SEPN1) is a type II transmembrane protein that senses ER calcium fluctuations by binding this ion through a luminal EF-hand domain. In vitro and in vivo experiments show that via this domain, SEPN1 responds to diminished luminal calcium levels, dynamically changing its oligomeric state and enhancing its redox-dependent interaction with cellular partners, including the ER calcium pump sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). Importantly, single amino acid substitutions in the EF-hand domain of SEPN1 identified as clinical variations are shown to impair its calcium-binding and calcium-dependent structural changes, suggesting a key role of the EF-hand domain in SEPN1 function. In conclusion, SEPN1 is a ER calcium sensor that responds to luminal calcium depletion, changing its oligomeric state and acting as a reductase to refill ER calcium stores., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)
- Published
- 2020
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