Structural features of STIM and Orai underlying store-operated calcium entry

Store-operated calcium entry (SOCE) through Orai channels is triggered by receptor-stimulated depletion of Ca²⁺ from the ER. Orai1 is unique in terms of its activation mechanism, biophysical properties, and structure, and its precise regulation is essential for human health. Recent studies have begun to reveal the structural basis of the major steps in the SOCE pathway and how the system is reliably suppressed in resting cells but able to respond robustly to ER Ca²⁺ depletion. In this review, we discuss current models describing the activation of ER Ca²⁺ sensor STIM1, its binding to Orai1, propagation of the binding signal from the channel periphery to the central pore, and the resulting conformational changes underlying opening of the highly Ca²⁺ selective Orai1 channel.