Calcium is an important second messenger that is involved in almost all cellular processes. Disruptions in the regulation of intracellular Ca2+ levels ([Ca2+]i) adversely impact normal physiological function and can contribute to various diseased conditions. STIM and Orai proteins play important roles in maintaining [Ca2+]i through store-operated Ca2+ entry (SOCE), with STIM being the primary regulatory protein that governs the function of Orai channels. STIM1 and STIM2 are single-pass ER-transmembrane proteins with their N- and C-termini located in the ER lumen and cytoplasm, respectively. The N-terminal EF-SAM domain of STIMs senses [Ca2+]ER changes, while the C-terminus mediates clustering in ER-PM junctions and gating of Orai1. ER-Ca2+ store depletion triggers activation of the STIM proteins, which involves their multimerization and clustering in ER-PM junctions, where they recruit and activate Orai1 channels. In this review, we will discuss the structure, organization, and function of EF-hand motifs and the SAM domain of STIM proteins in relation to those of other eukaryotic proteins.
Keywords: EF-hand; SAM; SOCE; STIM1; STIM2; calcium signaling.