The molecular choreography of STIM1–ORAI1 coupling is initiated by endoplasmic reticulum (ER) Ca2+ store depletion with subsequent oligomerization of the STIM1 ER-luminal domain, followed by its redistribution towards the plasma membrane to gate ORAI1 channels.
The mechanistic underpinnings of this inside-out Ca2+signalling were largely undefined. Authors show that local rearrangement, rather than alteration in the oligomeric state of STIM1-TM, prompts conformational changes in the cytosolic juxtamembrane coiled-coil region.
Importantly, authors further identify critical residues within the cytoplasmic domain of STIM1 (STIM1-CT) that entailautoinhibition. On the basis of these findings, authors propose a model in which STIM1-TM reorganization switches STIM1-CT into an extended conformation, thereby projecting the ORAI-activating domain to gate ORAI1 channels.