STIM1 and Orai1 are key components of the Ca2+-release activated Ca2+ (CRAC) current. Orai1, which represents the subunit forming the CRAC channel complex, is activated by the ER resident Ca2+ sensor STIM1. The genetically inherited Stormorken syndrome disease has been associated with the STIM1 single point R304W mutant. The resulting constitutive activation of Orai1 mainly involves the CRAC-activating domain CAD/SOAR of STIM1, the exposure of which is regulated by the molecular interplay between three cytosolic STIM1 coiled-coil (CC) domains. Here we present a dual mechanism by which STIM1 R304W attains the pathophysiological, constitutive activity eliciting the Stormorken syndrome. The R304W mutation induces a helical elongation within the CC1 domain, which together with an increased CC1 homomerization, destabilize the resting state of STIM1. This culminates, even in the absence of store depletion, in structural extension and CAD/SOAR exposure of STIM1 R304W leading to constitutive CRAC channel activation and Stormorken disease.

Department of Physiology and Pharmacology University of Western Ontario London ON N6A 5C1 Canada

Institute of Biophysics Johannes Kepler University Linz Gruberstrasse 40 4020 Linz Austria

Institute of Organic Chemistry Johannes Kepler University Linz Altenbergerstrasse 69 4040 Linz Austria

Institute of Organic Chemistry Johannes Kepler University Linz Altenbergerstrasse 69 4040 Linz Austria Faculty of Science University of South Bohemia Branišovská 1645 31A 370 05 České Budějovice Czech Republic

Princess Margaret Cancer Center University Health Network Toronto ON M5G 1L7 Canada Department of Medical Biophysics University of Toronto Toronto ON M5G 1L7 Canada

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