Selenoprotein N is an endoplasmic reticulum calcium sensor that links luminal calcium levels to a redox activity

Proc Natl Acad Sci U S A. 2020 Sep 1;117(35):21288-21298. doi: 10.1073/pnas.2003847117. Epub 2020 Aug 17.


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.

Keywords: SEPN1; calcium sensor; endoplasmic reticulum; stress of the endoplasmic reticulum.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcium / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • HeLa Cells
  • Humans
  • Intracellular Calcium-Sensing Proteins / genetics
  • Intracellular Calcium-Sensing Proteins / metabolism*
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Oxidation-Reduction
  • Selenoproteins / genetics
  • Selenoproteins / metabolism*


  • Intracellular Calcium-Sensing Proteins
  • Muscle Proteins
  • SELENON protein, human
  • Selenoproteins
  • Calcium