Modulation of STIM1 and capacitative Ca2+ entry by the endoplasmic reticulum luminal oxidoreductase ERp57

STIM1 is an endoplasmic reticulum (ER) membrane Ca2+ sensor responsible for activation of store-operated Ca2+ influx. We discovered that STIM1 oligomerization and store-operated Ca2+ 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 Ca2+ entry. This is the first demonstration of a protein involved in ER intraluminal regulation of STIM1.