title: Neddylation positively regulates the ubiquitin E3 ligase activity of parkin.
abstract: Mutations in the parkin gene underlie a familial form of Parkinson's disease known as autosomal recessive juvenile Parkinsonism (AR-JP). Dysfunction of parkin, a ubiquitin E3 ligase, has been implicated in the accumulation of ubiquitin proteasome system-destined substrates and eventually leads to cell death. However, regulation of parkin enzymatic activity is incompletely understood. Here we investigated whether the ubiquitin E3 ligase activity of parkin could be regulated by neddylation. We found that parkin could be a target of covalent modification with NEDD8, a ubiquitin-like posttranslational modifier. In addition, NEDD8 attachment caused an increase of parkin activity through the increased binding affinity for ubiquitin-conjugating E2 enzyme as well as the enhanced formation of the complex containing parkin and substrates. These findings point to the functional importance of NEDD8 and suggest that neddylation is one to the diverse modes of parkin regulation, potentially linking it to the pathogenesis of AR-JP.
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Um
authors.forename: Kyung Ah
authors.initials: KA
authors.lastname: Han
authors.forename: Eunju
authors.initials: E
authors.lastname: Im
authors.forename: Yohan
authors.initials: Y
authors.lastname: Oh
authors.forename: Kyule
authors.initials: K
authors.lastname: Lee
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Chung
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D047468:Immunoprecipitation; D007976:Leupeptins / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D000075687:NEDD8 Protein; D009447:Neuroblastoma / Q000473:pathology; D009498:Neurotoxins / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D012844:Sincalide / Q000378:metabolism; D013234:Stem Cells; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
chemical_list: D007976:Leupeptins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D009498:Neurotoxins; D011500:Protein Synthesis Inhibitors; D034741:RNA, Small Interfering; D014452:Ubiquitins; D003513:Cycloheximide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D012844:Sincalide; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde