Figure 1. STIM1 targeting through the STIM–Orai‐activating region (SOAR) vs. its proline‐/serine‐rich domain
At rest, the ER is Ca2+ replete and STIM1 dimers are inactive (left). Under these conditions, Ca2+ is bound to the luminal EF hands and SOAR associates closely with CC1, limiting the access of STIM1 to PM localized targets. Decrease in the luminal Ca2+ levels (middle) causes dissociation of Ca2+ from the STIM1 EF hands, leading to a conformational change, extension of the protein toward the PM, and availability of both the SOAR and P/S domain to targets within the PM. Through SOAR (middle), STIM1 associates directly with Orai1 and CaV1.2, leading to their activation and inhibition, respectively. Orai1 also activates adenylate cyclase 8 (AC8). Through the P/S domain (right), STIM1 associates with both the plasma membrane Ca2+/ATPase (PMCA4b) and adenylate cyclase 6 (AC6), leading to their inhibition and activation, respectively. Inset: Identification of STIM1 domains. Poly‐K, lysine‐rich domain; P/S domain, proline‐/serine‐rich domain; SOAR, STIM–Orai1‐activating region; CC1, coiled‐coil 1; TM, transmembrane domain; SAM, sterile α motif; cEF, canonical EF hand; and hEF, homologous EF hand.