RT Journal Article SR Electronic T1 Structure-based design and characterization of Parkin-activating mutations JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202201419 DO 10.26508/lsa.202201419 VO 6 IS 6 A1 Michael U Stevens A1 Nathalie Croteau A1 Mohamed A Eldeeb A1 Odetta Antico A1 Zhi Wei Zeng A1 Rachel Toth A1 Thomas M Durcan A1 Wolfdieter Springer A1 Edward A Fon A1 Miratul MK Muqit A1 Jean-François Trempe YR 2023 UL https://www.life-science-alliance.org/content/6/6/e202201419.abstract AB Autosomal recessive mutations in the Parkin gene cause Parkinson’s disease. Parkin encodes an ubiquitin E3 ligase that functions together with the kinase PINK1 in a mitochondrial quality control pathway. Parkin exists in an inactive conformation mediated by autoinhibitory domain interfaces. Thus, Parkin has become a target for the development of therapeutics that activate its ligase activity. Yet, the extent to which different regions of Parkin can be targeted for activation remained unknown. Here, we have used a rational structure-based approach to design new activating mutations in both human and rat Parkin across interdomain interfaces. Out of 31 mutations tested, we identified 11 activating mutations that all cluster near the RING0:RING2 or REP:RING1 interfaces. The activity of these mutants correlates with reduced thermal stability. Furthermore, three mutations V393D, A401D, and W403A rescue a Parkin S65A mutant, defective in mitophagy, in cell-based studies. Overall our data extend previous analysis of Parkin activation mutants and suggests that small molecules that would mimic RING0:RING2 or REP:RING1 destabilisation offer therapeutic potential for Parkinson’s disease patients harbouring select Parkin mutations.