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Mutations in protein kinase Cγ promote spinocerebellar ataxia type 14 by impairing kinase autoinhibition.
Pilo, Caila A; Baffi, Timothy R; Kornev, Alexandr P; Kunkel, Maya T; Malfavon, Mario; Chen, Dong-Hui; Rossitto, Leigh-Ana; Chen, Daniel X; Huang, Liang-Chin; Longman, Cheryl; Kannan, Natarajan; Raskind, Wendy H; Gonzalez, David J; Taylor, Susan S; Gorrie, George; Newton, Alexandra C.
Afiliación
  • Pilo CA; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92037, USA.
  • Baffi TR; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92037, USA.
  • Kornev AP; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92037, USA.
  • Kunkel MT; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92037, USA.
  • Malfavon M; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92037, USA.
  • Chen DH; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92037, USA.
  • Rossitto LA; Department of Neurology, University of Washington, Seattle, WA 98195, USA.
  • Chen DX; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92037, USA.
  • Huang LC; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92037, USA.
  • Longman C; Department of Neurology, University of Washington, Seattle, WA 98195, USA.
  • Kannan N; Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA.
  • Raskind WH; Queen Elizabeth University Hospital, Glasgow, Scotland G51 4TF, UK.
  • Gonzalez DJ; Institute of Bioinformatics, University of Georgia, Athens, GA 30602, USA.
  • Taylor SS; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
  • Gorrie G; Department of Medicine/Medical Genetics, University of Washington, Seattle, WA 98195, USA.
  • Newton AC; Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
Sci Signal ; 15(753): eabk1147, 2022 Sep 27.
Article en En | MEDLINE | ID: mdl-36166510
Spinocerebellar ataxia type 14 (SCA14) is a neurodegenerative disease caused by germline variants in the diacylglycerol (DAG)/Ca2+-regulated protein kinase Cγ (PKCγ), leading to Purkinje cell degeneration and progressive cerebellar dysfunction. Most of the identified mutations cluster in the DAG-sensing C1 domains. Here, we found with a FRET-based activity reporter that SCA14-associated PKCγ mutations, including a previously undescribed variant, D115Y, enhanced the basal activity of the kinase by compromising its autoinhibition. Unlike other mutations in PKC that impair its autoinhibition but lead to its degradation, the C1 domain mutations protected PKCγ from such down-regulation. This enhanced basal signaling rewired the brain phosphoproteome, as revealed by phosphoproteomic analysis of cerebella from mice expressing a human SCA14-associated H101Y mutant PKCγ transgene. Mutations that induced a high basal activity in vitro were associated with earlier average age of onset in patients. Furthermore, the extent of disrupted autoinhibition, but not agonist-stimulated activity, correlated with disease severity. Molecular modeling indicated that almost all SCA14 variants not within the C1 domain were located at interfaces with the C1B domain, suggesting that mutations in and proximal to the C1B domain are a susceptibility for SCA14 because they uniquely enhance PKCγ basal activity while protecting the enzyme from down-regulation. These results provide insight into how PKCγ activation is modulated and how deregulation of the cerebellar phosphoproteome by SCA14-associated mutations affects disease progression.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxias Espinocerebelosas / Diglicéridos Límite: Animals / Humans Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxias Espinocerebelosas / Diglicéridos Límite: Animals / Humans Idioma: En Revista: Sci Signal Asunto de la revista: CIENCIA / FISIOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos