TY - JOUR
T1 - Structure-based design and characterization of Parkin-activating mutations
AU - Stevens, Michael U.
AU - Croteau, Nathalie
AU - Eldeeb, Mohamed A.
AU - Antico, Odetta
AU - Zeng, Zhi Wei
AU - Toth, Rachel
AU - Durcan, Thomas M.
AU - Springer, Wolfdieter
AU - Fon, Edward A.
AU - Muqit, Miratul M.K.
AU - Trempe, Jean François
N1 - Publisher Copyright:
© 2023 Stevens et al.
PY - 2023
Y1 - 2023
N2 - 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.
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.
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U2 - 10.26508/LSA.202201419
DO - 10.26508/LSA.202201419
M3 - Article
C2 - 36941054
AN - SCOPUS:85150751782
SN - 2575-1077
VL - 6
JO - Life Science Alliance
JF - Life Science Alliance
IS - 6
M1 - e202201419
ER -