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

Abstract

STIM1 is an endoplasmic reticulum (ER) membrane Ca 2þ sensor responsible for activation of store-operated Ca 2þ influx. We discovered that STIM1 oligomerization and store-operated Ca 2þ 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 2þ entry. This is the first demonstration of a protein involved in ER intraluminal regulation of STIM1.

Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function

“…The lack of STIM1, however, likely represents a more chronic or sustained ER stress, and as such additional studies are required to understand the mechanism(s) contributing to the lower levels of BiP/GRP78. Nevertheless, these results are consistent with other reports indicating that STIM1 may mediate ER remodeling (11), as well as associate with several additional ER chaperone proteins such as stanniocalcin 2 (42) and the ER oxidoreductase ERp57 (32).…”

Junctate boosts phagocytosis by recruiting endoplasmic reticulum Ca2+ stores near phagosomes

“…−/− MEFs, generated through targeted gene disruption (Prins et al, 2011), and wild-type MEF control cells were a kind gift from Dr Marek Michalak (University of Alberta, Canada). YFP-tagged junctate was a kind gift from Dr Susan Treves (University of Basel, Switzerland).…”

Calcium and bioenergetics: from endoplasmic reticulum to mitochondria

“…Upon depletion of ER Ca 2' stores and disassociation of Ca 2' from STIM1, the protein undergoes oligomerization at sites immediately adjacent to the plasma membrane, and binds Orai, a SOCE channel (Hewavitharana et al 2007). Thus, the STIM1ÁOrai complex SOCE refills ER stores with Ca 2' funneled from the extracellular space directly into the ER lumen (Lewis 2007;Prins et al 2011). A large portion of the luminal ER Ca 2' is free (50Á800 mM) (Bygrave and Benedetti 1996), and this allows for rapid diffusion of Ca 2' throughout the ER lumen.…”