title: Autoregulation of Parkin activity through its ubiquitin-like domain.
abstract: Parkin is an E3-ubiquitin ligase belonging to the RBR (RING-InBetweenRING-RING family), and is involved in the neurodegenerative disorder Parkinson's disease. Autosomal recessive juvenile Parkinsonism, which is one of the most common familial forms of the disease, is directly linked to mutations in the parkin gene. However, the molecular mechanisms of Parkin dysfunction in the disease state remain to be established. We now demonstrate that the ubiquitin-like domain of Parkin functions to inhibit its autoubiquitination. Moreover pathogenic Parkin mutations disrupt this autoinhibition, resulting in a constitutively active molecule. In addition, we show that the mechanism of autoregulation involves ubiquitin binding by a C-terminal region of Parkin. Our observations provide important molecular insights into the underlying basis of Parkinson's disease, and in the regulation of RBR E3-ligase activity.
authors.affiliation: Protein Structure and Function Laboratory, Cancer Research UK, London Research Institute, London, UK.
authors.forename: Viduth K
authors.initials: VK
authors.lastname: Chaugule
authors.forename: Lynn
authors.initials: L
authors.lastname: Burchell
authors.forename: Kathryn R
authors.initials: KR
authors.lastname: Barber
authors.forename: Ateesh
authors.initials: A
authors.lastname: Sidhu
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Leslie
authors.forename: Gary S
authors.initials: GS
authors.lastname: Shaw
authors.forename: Helen
authors.initials: H
authors.lastname: Walden
mesh_terms: D000595:Amino Acid Sequence; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein