Structure-based design and characterization of Parkin-activating mutations

Michael U. Stevens, Nathalie Croteau, Mohamed A. Eldeeb, Odetta Antico, Zhi Wei Zeng, Rachel Toth, Thomas M. Durcan, Wolfdieter Springer, Edward A. Fon (Lead / Corresponding author), Miratul M. K. Muqit (Lead / Corresponding author), Jean-François Trempe (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
61 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article numbere202201419
Number of pages16
JournalLife Science Alliance
Volume6
Issue number6
Early online date20 Mar 2023
DOIs
Publication statusPublished - Jun 2023

Keywords

  • Humans
  • Animals
  • Rats
  • Parkinson Disease/genetics
  • Ubiquitin-Protein Ligases/genetics
  • Mutation/genetics
  • Ubiquitin/metabolism
  • Gain of Function Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Health, Toxicology and Mutagenesis
  • Plant Science
  • Ecology

Fingerprint

Dive into the research topics of 'Structure-based design and characterization of Parkin-activating mutations'. Together they form a unique fingerprint.

Cite this