A dual mechanism promotes switching of the Stormorken STIM1 R304W mutant into the activated state

Marc Fahrner (), Michael Stadlbauer, Martin Muik, Petr Rathner, Peter Stathopulos, Mitsu Ikura, Norbert Müller and Christoph Romanin ()
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Marc Fahrner: Johannes Kepler University Linz
Michael Stadlbauer: Johannes Kepler University Linz
Martin Muik: Johannes Kepler University Linz
Petr Rathner: Johannes Kepler University Linz
Peter Stathopulos: University of Western Ontario
Mitsu Ikura: University Health Network
Norbert Müller: Johannes Kepler University Linz
Christoph Romanin: Johannes Kepler University Linz

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03062-w

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