A Deep Dive into the N-Terminus of STIM Proteins: Structure-Function Analysis and Evolutionary Significance of the Functional Domains.

Calcium is an important second messenger that is involved in almost all cellular processes. Disruptions in the regulation of intracellular Ca levels ([Ca]) adversely impact normal physiological function and can contribute to various diseased conditions. STIM and Orai proteins play important roles in maintaining [Ca] through store-operated Ca 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 [Ca] changes, while the C-terminus mediates clustering in ER-PM junctions and gating of Orai1. ER-Ca 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.