CRACking the structure of Orai

Correspondence to: Andrew P. Braun Email: [email protected] Calcium (Ca) is well recognized as a key second messenger in a variety of eukaryotic signal transduction pathways, and nature has developed a number of regulatory mechanisms to mediate its cellular influx and efflux and its homeostasis within the cell. Stimulus-evoked release of Ca stored within internal organelles (i.e., endoplasmic and/or sacroplasmic reticulum) is known to trigger the subsequent influx of external Ca as a means to replenish the internal store, and a flurry of studies over the past 5–10 y have demonstrated that this influx process involves two main molecular players; STIM1, a transmembrane Ca sensor protein localized to the internal storage organelle and Orai, an integral plasma membrane protein that mediates Ca entry in response to store depletion. Cahalan and coworkers initially identified STIM1 as a novel Ca-binding protein through use of a comprehensive siRNA-based screen of candidate molecules in Drosophila S2 cells whose loss could impact evoked Ca entry. A year later, Orai was discovered through genetic mapping studies of a novel mutation associated with impaired lymphocyte function and severe immunodeficiency in patients, and was subsequently found to be an integral plasma membrane component of the calcium influx channel. The latter studies revealed that lymphocyte dysfunction was associated with a loss of evoked calcium influx in these cells, which correlated with a single Arg to Trp amino acid substitution in the first predicted transmembrane segment of Orai1. More recently, investigators have reported that Orai protein CRACking the structure of Orai