Stromal interaction molecules (STIMs) function as endoplasmic reticulum calcium (Ca2+) sensors that differentially regulate plasma membrane Ca2+ release activated Ca2+ channels in various cells. STIM1 stimulates calcium ion (Ca2+) entry through plasma membrane Orai1 channels in response to decreased Ca2+ concentrations in the endoplasmic reticulum lumen, and STIM1 and Orai1 are important for T cell activation, platelet aggregation and skeletal muscle development. <br>The N-terminal luminal segment of STIM1 contains EF-hand and SAM (sterile α motif) domain and the C-terminal segment contains two putative coiled-coil domains (CC1 and CC2), as well as several acidic, serine-proline-rich, and basic segments. An acidic motif within the coiled-coil region keeps STIM1 inactive via an intramolecular interaction with a basic sequence within the Orai1 activating domain (SOAR) that has been identified as key for Orai1 activation. The oligomerization of STIM1 unmasks the SOAR domain by breaking the intramolecular interaction that keeps it inactive in the quiescent STIM1 molecule. <br> Furthermore, it has been reported that stabilizing EF-SAM domains within full-length STIM1 inhibit Ca2+ release-activated Ca2+ (CRAC) entry. The EF-hand together with the SAM domains (i.e., EF-SAM)s in the luminal region of all STIMs are responsible for Ca2+ sensing and initiating the molecular reorganization at ER-PM junctions responsible for store-operated Ca2+ entry.