Modulation of STIM1 and capacitative Ca 2+ entry by the endoplasmic reticulum luminal oxidoreductase ERp57

STIM1 is an endoplasmic reticulum (ER) membrane Ca 2+ sensor responsible for activation of store‐operated Ca 2+ influx. We discovered that STIM1 oligomerization and store‐operated Ca 2+ entry (SOC) are modulated by the ER oxidoreductase ERp57. ERp57 interacts with the ER luminal domain of STIM1, with this interaction involving two conserved cysteine residues, C 49 and C 56 . SOC is accelerated in the absence of ERp57 and inhibited in C 49 and C 56 mutants of STIM1. We show that ERp57, by ER luminal interaction with STIM1, has a modulatory role in capacitative Ca 2+ entry. This is the first demonstration of a protein involved in ER intraluminal regulation of STIM1.