Store-Operated Calcium Channels: From Function to Structure and Back Again

Store-operated calcium (Ca 2+ ) entry (SOCE) occurs through a widely distributed family of ion channels activated by the loss of Ca 2+ from the endoplasmic reticulum (ER). The best understood of these is the Ca 2+ release-activated Ca 2+ (CRAC) channel, which is notable for its unique activation mechanism as well as its many essential physiological functions and the diverse pathologies that result from dysregulation. In response to ER Ca 2+ depletion, CRAC channels are formed through a diffusion trap mechanism at ER-plasma membrane (PM) junctions, where the ER Ca 2+ -sensing stromal interaction molecule (STIM) proteins bind and activate hexamers of Orai pore-forming proteins to trigger Ca 2+ entry. Cell biological studies are clarifying the architecture of ER-PM junctions, their roles in Ca 2+ and lipid transport, and functional interactions with cytoskeletal proteins. Molecular structures of STIM and Orai have inspired a multitude of mutagenesis and electrophysiological studies that reveal potential mechanisms for how STIM is toggled between inactive and active states, how it binds and activates Orai, and the importance of STIM-binding stoichiometry for opening the channel and establishing its signature characteristics of extremely high Ca 2+ selectivity and low Ca 2+ conductance.