Mechanistic view on domains mediating STIM1–Orai coupling

Summary:  Calcium (Ca2+) entry into non‐excitable cells is mainly carried by store‐operated channels, which serve essential functions ranging from regulation of transcription to cell growth. The best‐characterized store‐operated current, initially discovered in T lymphocytes and mast cells, is the Ca2+ release‐activated Ca2+ (CRAC) current. The search for the molecular components of the CRAC channel has recently identified stromal interaction molecule 1 (STIM1) as the Ca2+ sensor in the endoplasmic reticulum (ER) and Orai1 as the CRAC channel pore. ER store depletion results in formation of STIM1 puncta that trigger Ca2+ influx via Orai1 channels. This review covers the role of domains within STIM1 and Orai and enlightens their function in the STIM1/Orai coupling process. Moreover, a molecular interpretation focuses on interactions between cytosolic portions of STIM1 and Orai together with a mechanistic view on the loss of function of the SCID (severe combined immunodeficiency)‐linked Orai1 R91W mutant channel. The architecture of the selectivity filter of Orai channels is finally elucidated based on permeation properties of Orai pore mutants.

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