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Activation of STIM1-Orai1 Involves an Intramolecular Switching Mechanism

A cytoplasmic domain in STIM1 acts as a decoy to block the ability of STIM1 to bind to and activate Orai1. An Intramolecular STIM1 Inhibitor Loss of Ca2+ from stores within the endoplasmic reticulum (ER) elicits translocation of STIM1 (stromal interacting molecule 1), a transmembrane ER protein, to a region of the ER near the plasma membrane, enabling its interaction with the Orai1 channel. This interaction leads to Orai1 activation—and thereby Ca2+ influx to elicit intracellular Ca2+ signals and replenish the depleted stores. In an exploration of the mechanisms involved in switching STIM1 from the inactive “resting” form found in cells with replete Ca2+ stores to the active form, Korzeniowski et al. identified a region of the STIM1 cytoplasmic domain required for maintenance of its inactive state and noted its resemblance to a region of Orai1 implicated in its interaction with STIM1. Mutational analysis, in combination with Förster resonance energy transfer and Ca2+ imaging, led them to propose a model in which this region acted as a decoy to block the ability of STIM1 to bind to and activate Orai1. Stromal interaction molecule 1 (STIM1) stimulates calcium ion (Ca2+) entry through plasma membrane Orai1 channels in response to decreased Ca2+ concentrations in the endoplasmic reticulum lumen. We identified an acidic motif within the STIM1 coiled-coil region that keeps its Ca2+ activation domain [Ca2+ release–activated Ca2+ (CRAC) activation domain/STIM1-Orai activating region (CAD/SOAR)]—a cytoplasmic region required for its activation of Orai1—inactive. The sequence of the STIM1 acidic motif shows substantial similarity to that of the carboxyl-terminal coiled-coil segment of Orai1, which is the postulated site of interaction with STIM1. Mutations within this acidic region rendered STIM1 constitutively active, whereas mutations within a short basic segment of CAD/SOAR prevented Orai1 activation. We propose that the CAD/SOAR domain is released from an intramolecular clamp during STIM1 activation, allowing the basic segment to activate Orai1 channels. This evolutionarily conserved mechanism of STIM1 activation resembles the regulation of protein kinases by intramolecular silencing through pseudosubstrate binding.