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.

• MeSH
• abnormální erytrocyty metabolismus   patologie   MeSH
• bakteriální proteiny genetika   metabolismus   MeSH
• bodová mutace * MeSH
• dyslexie genetika   metabolismus   patologie   MeSH
• exprese genu MeSH
• HEK293 buňky MeSH
• ichtyóza genetika   metabolismus   patologie   MeSH
• interakční proteinové domény a motivy MeSH
• iontový transport MeSH
• konformace proteinů, alfa-helix MeSH
• lidé MeSH
• luminescentní proteiny genetika   metabolismus   MeSH
• metoda terčíkového zámku MeSH
• migréna genetika   metabolismus   patologie   MeSH
• mióza genetika   metabolismus   patologie   MeSH
• molekulární modely MeSH
• multimerizace proteinu MeSH
• nádorové proteiny chemie   genetika   metabolismus   MeSH
• protein ORAI1 chemie   genetika   metabolismus   MeSH
• protein STIM1 chemie   genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• rekombinantní proteiny chemie   genetika   metabolismus   MeSH
• reportérové geny MeSH
• sekvence aminokyselin MeSH
• slezina abnormality   metabolismus   patologie   MeSH
• substituce aminokyselin MeSH
• svalová únava genetika   MeSH
• trombocytopatie genetika   metabolismus   patologie   MeSH
• vápník chemie   metabolismus   MeSH
• vazba proteinů MeSH
• vazebná místa MeSH
• zelené fluorescenční proteiny genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH