Structure-based design and characterization of Parkin activating mutations
Structure-based design and characterization of Parkin activating mutations
Abstract Human autosomal recessive mutations in the Parkin gene are causal for Parkinson’s disease (PD). Parkin encodes a ubiquitin E3 ligase that functions together with the PD associated kinase, PINK1, in a mitochondrial quality control pathway. Structural studies reveal that Parkin exists in an inactive conformation mediated by multiple autoinhibitory domain interfaces. Here we have performed comprehensive mutational analysis of both human and rat Parkin to unbiasedly determine Parkin activating mutations across all major autoinhibitory interfaces. Out of 31 mutations tested, we identify 11 activating mutations clustered near the RING0:RING2 or REP:RING1 interfaces, which reduce the thermal stability of Parkin. Of these, we demonstrate that three mutations, V393D, A401D, and W403A located at the REP:RING1 interface were able to completely rescue a Parkin S65A mutant, defective in mitophagy, in cell-based studies. Overall our data extends previous analysis of Parkin activation mutants and suggests that small molecules that mimic REP:RING1 destabilisation offer therapeutic potential for PD patients harbouring select Parkin mutations. Summary blurbParkin, an E3 ubiquitin ligase involved in Parkinson’s disease, is inactive in the basal state and is activated by PINK1 to mediate mitophagy. Here we characterized 31 mutations and discovered three that activate Parkin and rescue loss of PINK1 phosphorylation.
Stevens Michael U.、Croteau Nathalie、Zeng Zhi Wei、Durcan Thomas M.、Fon Edward A.、Springer Wolfdieter、Trempe Jean-Fran?ois、Muqit Miratul M. K.、Toth Rachel、Eldeeb Mohamed A.
MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of DundeeDepartment of Pharmacology & Therapeutics, McGill University||Centre de Recherche en Biologie StructuraleDepartment of Pharmacology & Therapeutics, McGill UniversityMcGill Parkinson Program, Montreal Neurological Institute, McGill UniversityMcGill Parkinson Program, Montreal Neurological Institute, McGill UniversityDepartment of Neuroscience, Mayo Clinic||Neuroscience PhD Program, Mayo Clinic Graduate School of Biomedical SciencesDepartment of Pharmacology & Therapeutics, McGill University||Centre de Recherche en Biologie StructuraleMRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of DundeeMRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of DundeeMcGill Parkinson Program, Montreal Neurological Institute, McGill University
神经病学、精神病学基础医学分子生物学
ParkinPINK1ubiquitinParkinson’s diseasemitochondrial quality controlmitophagy
Stevens Michael U.,Croteau Nathalie,Zeng Zhi Wei,Durcan Thomas M.,Fon Edward A.,Springer Wolfdieter,Trempe Jean-Fran?ois,Muqit Miratul M. K.,Toth Rachel,Eldeeb Mohamed A..Structure-based design and characterization of Parkin activating mutations[EB/OL].(2025-03-28)[2025-05-25].https://www.biorxiv.org/content/10.1101/2022.02.22.481412.点此复制
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