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

Nature Communications
Marc FahrnerChristoph Romanin

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.

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Citations

Nov 13, 2018·Médecine sciences : M/S·Johann Böhm, Jocelyn Laporte
Feb 15, 2019·Journal of Child Neurology·Ang LiAndrew J Waclawik
Nov 2, 2019·Disease Models & Mechanisms·Celia Cordero-SanchezArmando A Genazzani
Mar 25, 2019·European Biophysics Journal : EBJ·Adéla KrizovaIsabella Derler
Jul 3, 2020·International Journal of Environmental Research and Public Health·Giuliano MolinariElsa Nervo
Oct 28, 2018·International Journal of Molecular Sciences·Steve ChungPeter B Stathopulos
Oct 20, 2020·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Georges Arielle PecheJohann Böhm
Aug 22, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Isaac JardinJuan A Rosado
Nov 24, 2020·Current Opinion in Physiology·Marc FahrnerChristoph Romanin
Oct 28, 2020·Nature Chemical Biology·Petr RathnerNorbert Müller
Jan 6, 2021·International Journal of Molecular Sciences·Herwig GrabmayrMarc Fahrner
Oct 22, 2020·Cell Reports·Christine Silvia GibhardtIvan Bogeski
Aug 20, 2021·Frontiers in Neurology·Li-Jun JiangZan-Hua Rong
Aug 22, 2021·Biomolecular NMR Assignments·Agrim GuptaNorbert Müller
Aug 28, 2021·Cells·Inbal Dagan, Raz Palty
Sep 10, 2021·Cellular and Molecular Life Sciences : CMLS·Carmen HöglingerIsabella Derler

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Methods Mentioned

BETA
nuclear magnetic resonance
FRET
fluorescence imaging
confocal microscopy
X-ray
circular dichroism
electrophoresis
NMR

Software Mentioned

FIRE
CAD
Visiview
TopSpin
MatLab

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