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Multiple Sequence Variants in STAC3 Affect Interactions with CaV1.1 and Excitation-Contraction Coupling.
Rufenach, Britany; Christy, Darren; Flucher, Bernhard E; Bui, Jennifer M; Gsponer, Jörg; Campiglio, Marta; Van Petegem, Filip.
Afiliación
  • Rufenach B; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • Christy D; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • Flucher BE; Department of Physiology and Medical Physics, Medical University of Innsbruck, 6020 Innsbruck, Austria.
  • Bui JM; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • Gsponer J; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • Campiglio M; Department of Physiology and Medical Physics, Medical University of Innsbruck, 6020 Innsbruck, Austria. Electronic address: marta.campiglio@i-med.ac.at.
  • Van Petegem F; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: filip.vanpetegem@gmail.com.
Structure ; 28(8): 922-932.e5, 2020 08 04.
Article en En | MEDLINE | ID: mdl-32492370
ABSTRACT
STAC3 is a soluble protein essential for skeletal muscle excitation-contraction (EC) coupling. Through its tandem SH3 domains, it interacts with the cytosolic II-III loop of the skeletal muscle voltage-gated calcium channel. STAC3 is the target for a mutation (W284S) that causes Native American myopathy, but multiple other sequence variants have been reported. Here, we report a crystal structure of the human STAC3 tandem SH3 domains. We analyzed the effect of five disease-associated variants, spread over both SH3 domains, on their ability to bind to the CaV1.1 II-III loop and on muscle EC coupling. In addition to W284S, we find the F295L and K329N variants to affect both binding and EC coupling. The ability of the K329N variant, located in the second SH3 domain, to affect the interaction highlights the importance of both SH3 domains in association with CaV1.1. Our results suggest that multiple STAC3 variants may cause myopathy.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Fisura del Paladar / Canales de Calcio Tipo L / Proteínas Adaptadoras Transductoras de Señales / Acoplamiento Excitación-Contracción / Hipertermia Maligna / Miotonía Congénita Límite: Humans Idioma: En Revista: Structure Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Año: 2020 Tipo del documento: Article País de afiliación: Canadá

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Fisura del Paladar / Canales de Calcio Tipo L / Proteínas Adaptadoras Transductoras de Señales / Acoplamiento Excitación-Contracción / Hipertermia Maligna / Miotonía Congénita Límite: Humans Idioma: En Revista: Structure Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA / BIOTECNOLOGIA Año: 2020 Tipo del documento: Article País de afiliación: Canadá