title: Parkin directly modulates 26S proteasome activity.
abstract: Parkinson's disease (PD) is a common neurodegenerative disease that involves the deterioration of dopaminergic neurons in the substantia nigra pars compacta. Although the etiology of PD remains poorly understood, recent genetic, postmortem, and experimental evidence shows that abnormal protein accumulation and subsequent aggregate formation are prominent features of both sporadic and familial PD. While proteasome dysfunction is observed in PD, diverse mutations in the parkin gene are linked to early-onset autosomal-recessive forms of familial PD. We demonstrate that parkin, an E3 ubiquitin ligase, activates the 26S proteasome in an E3 ligase activity-independent manner. Furthermore, an N-terminal ubiquitin-like domain within parkin is critical for the activation of the 26S proteasome through enhancing the interaction between 19S proteasomal subunits, whereas the PD-linked R42P mutant abolishes this action. The current findings point to a novel role for parkin for 26S proteasome assembly and suggest that parkin mutations contribute to the proteasomal dysfunction in PD.
authors.affiliation: Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Um
authors.forename: Eunju
authors.initials: E
authors.lastname: Im
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Boram
authors.initials: B
authors.lastname: Min
authors.forename: Lang
authors.initials: L
authors.lastname: Yoo
authors.forename: Jiho
authors.initials: J
authors.lastname: Yoo
authors.forename: Hermann
authors.initials: H
authors.lastname: Lübbert
authors.forename: Christine
authors.initials: C
authors.lastname: Stichel-Gunkel
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.forename: Jong Bok
authors.initials: JB
authors.lastname: Yoon
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Chung
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation / Q000235:genetics; D005808:Genes, Recessive; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D029721:Drosophila Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C487430:park protein, Drosophila
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