Post translational modification of Parkin

Abstract

Mutations in the gene encoding for the E3 ubiquitin ligase Parkin are associated to a rare form of familiar autosomal recessive Parkinsonism. Despite decades of research on the Parkin protein, whose structure has been recently solved, little is known about the specific signalling pathways that lead to Parkin activation. Parkin activity spans from mitochondria quality control to tumor suppression and stress protection; it is thus tempting to hypothesize that the broad impact of Parkin on cellular physiology might be the result of different post translational modifications that can be controlled by balanced opposing events. Sequence alignment of Parkin from different species indicates high homology between domains across Parkin orthologs and identifies highly conserved amino acid residues that, if modified, impinge on Parkin functions. In this review, we summarize findings on post translational modifications that have been shown to affect Parkin activity and stability.

Reviewers: This article was reviewed by Prof. Dr. Konstanze F. Winklhofer and by Prof. Thomas Simmen. Both reviewers have been nominated by Professor Luca Pellegrini.

Keywords: Parkin; Parkinson’s disease; Phosphorylation; Post translational modifications; Ubiquitination.

Fig. 1

Mapping of Parkin Post translational modifications. a Domain architecture of Parkin protein and sequence alignment from different species. We differently highlighted the amino acids that are post-translationally modified (green: sulfhydration; pink: phosphorylation; yellow: sulfonation). Parkin consists of five domains: UBL, ubiquitin-like domain; RING, really interesting new gene; IBR, in between RING; REP, repressor element of Parkin. b Schematic representation of the full-length structure mapping the post-translational modifications onto the structure. c Primary structure and domains of Parkin mapping the activating (“green”) and inactivating (“red”) post-translational modifications