%0 Journal Article
%T Selenoprotein N is an endoplasmic reticulum calcium sensor that links luminal calcium levels to a redox activity.
%A Chernorudskiy A
%A Varone E
%A Colombo SF
%A Fumagalli S
%A Cagnotto A
%A Cattaneo A
%A Briens M
%A Baltzinger M
%A Kuhn L
%A Bachi A
%A Berardi A
%A Salmona M
%A Musco G
%A Borgese N
%A Lescure A
%A Zito E
%J Proc Natl Acad Sci U S A
%V 117
%N 35
%D 09 2020 1
%M 32817544
%F 12.779
%R 10.1073/pnas.2003847117
%X 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.