Parkin binds the Rpn10 subunit of 26S proteasomes through its ubiquitin-like domain.
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.
Sakata
Eri
E
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.
Yamaguchi
Yoshiki
Y
Kurimoto
Eiji
E
Kikuchi
Jun
J
Yokoyama
Shigeyuki
S
Yamada
Shingo
S
Kawahara
Hiroyuki
H
Yokosawa
Hideyoshi
H
Hattori
Nobutaka
N
Mizuno
Yoshikuni
Y
Tanaka
Keiji
K
Kato
Koichi
K
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
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