Research ArticleCalcium signaling

Activation of STIM1-Orai1 Involves an Intramolecular Switching Mechanism

Sci. Signal.  16 Nov 2010:
Vol. 3, Issue 148, pp. ra82
DOI: 10.1126/scisignal.2001122

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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.

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