Orai1 (ORAI calcium release-activated calcium modulator 1); STIM1 (stromal interaction molecule 1) (Orai1; STIM1)

Orai1 is a plasma membrane protein that forms the pore of highly Ca2+-selective store-operated calcium entry (SOCE) channels, activated when the endoplasmic reticulum Ca2+ sensor STIM1 oligomerizes and binds to Orai1 upon ER store depletion. This interaction occurs at ER-plasma membrane junctions, where STIM1's CRAC activation domain (CAD) or SOAR engages Orai1's cytosolic C-terminal and N-terminal regions, triggering a cooperative wave of conformational changes across Orai1's four transmembrane domains to open the central pore lined by TM1. Orai1 channels exhibit extreme Ca2+ selectivity and mediate essential calcium influx for cellular processes like gene transcription, exocytosis, immune responses, and T-cell activation. STIM1, a single-pass ER membrane protein with luminal EF-hand and SAM domains, detects store depletion and links it to Orai1 gating. Dysfunctions, including loss-of-function mutations in Orai1 causing severe combined immunodeficiency (SCID) and gain-of-function mutations linked to tubular aggregate myopathy and Stormorken syndrome, underscore their roles in immunity and muscle function. Therapeutically, modulating Orai1/STIM1 is explored for immune disorders and inflammation, though challenges arise from the channel's allosteric gating and disease-associated mutations.

Other names

CRAC channel subunit (for Orai1)SOCE (store-operated calcium entry) components

Allosteric activation by STIM1 binding to Orai1 C-terminus and N-terminus, inducing conformational changes in transmembrane domains to open the Ca2+ pore