The calcium release activated calcium channel is activated by the endoplasmic reticulum-resident calcium sensor protein STIM1. On activation, STIM1 C terminus changes from an inactive, tight to an active, extended conformation. A coiled-coil clamp involving the CC1 and CC3 domains is essential in controlling STIM1 activation, with CC1 as the key entity. The nuclear magnetic resonance-derived solution structure of the CC1 domain represents a three-helix bundle stabilized by interhelical contacts, which are absent in the Stormorken disease-related STIM1 R304W mutant. Two interhelical sites between the CC1α1 and CC1α2 helices are key in controlling STIM1 activation, affecting the balance between tight and extended conformations. Nuclear magnetic resonance-directed mutations within these interhelical interactions restore the physiological, store-dependent activation behavior of the gain-of-function STIM1 R304W mutant. This study reveals the functional impact of interhelical interactions within the CC1 domain for modifying the CC1-CC3 clamp strength to control the activation of STIM1.

Department of Chemistry University of Florence Sesto Fiorentino Italy

Faculty of Science University of South Bohemia České Budějovice Czech Republic

Institute for Theoretical Physics Johannes Kepler University Linz Linz Austria

Institute of Biophysics Johannes Kepler University Linz Linz Austria

Institute of Inorganic Chemistry Johannes Kepler University Linz Linz Austria

Institute of Organic Chemistry Johannes Kepler University Linz Linz Austria

Magnetic Resonance Center Sesto Fiorentino Italy

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