STIM2 Induces Activated Conformation of STIM1 to Control Orai1 Function in ER-PM Junctions

Ca²⁺ entry mediated by the calcium channel, Orai1, provides critical Ca²⁺ signals that regulate cell function. The ER-Ca²⁺ sensor protein, STIM1, recruits and strongly activates Orai1 within ER-PM junctions. STIM2 is a poor activator of Orai1, and its physiological role is not well understood. Herein, we report a crucial function for STIM2 in inducing the activated conformation of STIM1. By using conformational sensors of STIM2 and STIM1, together with protein interaction and functional studies, we show that STIM2 is constitutively localized within ER-PM junctions in ER-Ca²⁺ store replete cells. Importantly, STIM2 traps STIM1 and triggers remodeling of STIM1 C terminus, causing STIM1/Orai1 coupling and enhancement of Orai1 function in cells with relatively high ER-[Ca²⁺]. The increase in Ca²⁺ entry controls Ca²⁺-dependent transcription factor, NFAT, activation at low [agonist]. Our findings reveal that STIM2 modulates STIM1/Orai1 function to tune the fidelity of receptor-evoked Ca²⁺ signaling and the physiological response of cells.