title: Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain.
abstract: Parkin, a product of the causative gene of autosomal-recessive juvenile parkinsonism (AR-JP), is a RING-type E3 ubiquitin ligase and has an amino-terminal ubiquitin-like (Ubl) domain. Although a single mutation that causes an Arg to Pro substitution at position 42 of the Ubl domain (the Arg 42 mutation) has been identified in AR-JP patients, the function of this domain is not clear. In this study, we determined the three-dimensional structure of the Ubl domain of parkin by NMR, in particular by extensive use of backbone (15)N-(1)H residual dipolar-coupling data. Inspection of chemical-shift-perturbation data showed that the parkin Ubl domain binds the Rpn10 subunit of 26S proteasomes via the region of parkin that includes position 42. Our findings suggest that the Arg 42 mutation induces a conformational change in the Rpn10-binding site of Ubl, resulting in impaired proteasomal binding of parkin, which could be the cause of AR-JP.
authors.affiliation: Department of Structural Biology and Biomolecular Engineering, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Sakata
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Eiji
authors.initials: E
authors.lastname: Kurimoto
authors.forename: Jun
authors.initials: J
authors.lastname: Kikuchi
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kawahara
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Yokosawa
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
authors.forename: Yoshikuni
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanaka
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D005808:Genes, Recessive; D006801:Humans; D008025:Ligases / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020734:Parkinsonian Disorders / Q000235:genetics; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011487:Protein Conformation; D016601:RNA-Binding Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; C498506:PSMD4 protein, human; D016601:RNA-Binding Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D008025:Ligases