Distinct gating mechanism of SOC channel involving STIM-Orai coupling and an intramolecular interaction of Orai in .

Store-operated calcium entry (SOCE), an important mechanism of Ca signaling in a wide range of cell types, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca stores and binds and activates Orai channels in the plasma membrane. This inside-out mechanism of Ca signaling raises an interesting question about the evolution of SOCE: How did these two proteins existing in different cellular compartments evolve to interact with each other? We investigated the gating mechanism of Orai channels. Our analysis revealed a mechanism of Orai gating by STIM binding to the intracellular 2-3 loop of Orai in that is radically different from Orai gating by STIM binding to the N and C termini of Orai in mammals. In addition, we found that the conserved hydrophobic amino acids in the 2-3 loop of Orai1 are important for the oligomerization and gating of channels and are regulated via an intramolecular interaction mechanism mediated by the N and C termini of Orai1. This study identifies a previously unknown SOCE mechanism in and suggests that, while the STIM-Orai interaction is conserved between invertebrates and mammals, the gating mechanism for Orai channels differs considerably.