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

Abstract

Summary: 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. : Subedi et al. describe a crucial role for STIM2 in enhancing Orai1 channel function when ER-[Ca2+] is not low enough to stimulate STIM1 activation. Under these conditions, STIM2 recruits STIM1 to ER-PM junctions and triggers a conformational change that causes STIM1 to interact with and induce strong activation of Orai1.