Abstract
Calcium signals drive an endless array of cellular responses including secretion, contraction, transcription, cell division, and growth. The ubiquitously expressed Orai family of plasma membrane (PM) ion channels mediate Ca2+ entry signals triggered by the Ca2+ sensor Stromal Interaction Molecule (STIM) proteins of the endoplasmic reticulum (ER). The 2 proteins interact within curiously obscure ER-PM junctions, driving an allosteric gating mechanism for the Orai channel. Although key to Ca2+ signal generation, molecular understanding of this activation process remain obscure. Crystallographic structural analyses reveal much about the exquisite hexameric core structure of Orai channels. But how STIM proteins bind to the channel periphery and remotely control opening of the central pore, has eluded such analysis. Recent studies apply both crystallography and single-particle cryogenic electron microscopy (cryo-EM) analyses to probe the structure of Orai mutants that mimic activation by STIM. The results provide new understanding on the open state of the channel and how STIM proteins may exert remote allosteric control of channel gating.
Highlights
The dimeric Stromal Interaction Molecule (STIM) proteins unfold when endoplasmic reticulum (ER) luminal Ca2+ decreases, becoming trapped in ER-plasma membrane (PM) junctions where they tether and activate hexameric Orai channels in the junction [3] (Fig 1A)
Activation was thought to involve a 2-pronged interaction in which strong STIM-Orai Activating Region (SOAR) binding to the Orai1 TM4 extension (TM4e) helix facilitated a further weak
The antiparallel pairing of the TM4e appears to involve hydrophobic interactions between the I316 and L319 residues in Drosophila Orai (dOrai). Could this interaction be induced by crystal packing forces? Could the Ile/Leu pairs merely be proximal as a result of a Zn2+-induced pairing? If unpairing of TM4e helices was important for STIM interaction, it might be expected that mutating the residues to prevent pairing would facilitate STIM binding
Summary
The dimeric STIM proteins unfold when ER luminal Ca2+ decreases, becoming trapped in ER-PM junctions where they tether and activate hexameric Orai channels in the junction [3] (Fig 1A). Orai channels have 4 transmembrane (TM) helices, of which the C-terminal innermost TM1 is the pore-forming helix, and the outermost TM4 extension (TM4e) provides a strong binding site for SOAR (Fig 1B) [1].
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