The intricate coupling between STIM proteins and Orai channels

Store-operated Ca²⁺ entry signals are critical for cellular regulation. This intricate signaling pathway involves coupling of proteins in two different membranes: the ER-resident Ca²⁺-sensing STIM proteins and the highly Ca²⁺-selective PM Orai channels. The molecular nature of the STIM-Orai coupling interface in ER-PM junctions and consequent Orai channel gating, are processes under intense study. We describe recent developments in determining the mechanism of Orai activation through the key STIM-Orai Activating Region (SOAR) of STIM1. We describe the unexpected unimolecular coupling of STIM with Orai and explain the observed variable stoichiometry of STIM-Orai interactions. We also define the discrete C-terminal regions in Orai channels that initially latch onto STIM proteins and mediate allosteric activation of the channel. A critical ‘nexus’ region closely associated with the STIM-activated C-terminus of Orai1, propagates the STIM-binding signal through the four tightly associated transmembrane helices of Orai1, finally to modify the pore-forming helices and effect channel opening.