title: NEDD8: a new ataxin-3 interactor.
abstract: Machado-Joseph disease (MJD/SCA3) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG tract in the coding portion of the ATXN3 gene. The presence of ubiquitin-positive aggregates of the defective protein in affected neurons is characteristic of this and most of the polyglutamine disorders. Recently, the accumulation of the neural precursor cell expressed developmentally downregulated 8 (NEDD8), a ubiquitin-like protein, in the inclusions of MJD brains was reported. Here, we report a new molecular interaction between wild-type ataxin-3 and NEDD8, using in vitro and in situ approaches. Furthermore, we show that this interaction is not dependent on the ubiquitin-interacting motifs in ataxin-3, since the presence of the Josephin domain is sufficient for the interaction to occur. The conservation of the interaction between the Caenorhabditis elegans ataxin-3 homologue (atx-3) and NEDD8 suggests its biological and functional relevance. Molecular docking studies of the NEDD8 molecule to the Josephin domain of ataxin-3 suggest that NEDD8 interacts with ataxin-3 in a substrate-like mode. In agreement, ataxin-3 displays deneddylase activity against a fluorogenic NEDD8 substrate.
authors.affiliation: UnIGENe-IBMC, Instituto de Biologia Molecular e Celular, University of Porto, 4150-180 Porto, Portugal.
authors.forename: Anabela
authors.initials: A
authors.lastname: Ferro
authors.forename: Ana Luísa
authors.initials: AL
authors.lastname: Carvalho
authors.forename: Andreia
authors.initials: A
authors.lastname: Teixeira-Castro
authors.forename: Carla
authors.initials: C
authors.lastname: Almeida
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Tomé
authors.forename: Luísa
authors.initials: L
authors.lastname: Cortes
authors.forename: Ana-João
authors.initials: AJ
authors.lastname: Rodrigues
authors.forename: Elsa
authors.initials: E
authors.lastname: Logarinho
authors.forename: Jorge
authors.initials: J
authors.lastname: Sequeiros
authors.forename: Sandra
authors.initials: S
authors.lastname: Macedo-Ribeiro
authors.forename: Patrícia
authors.initials: P
authors.lastname: Maciel
mesh_terms: D000818:Animals; D000067699:Ataxin-3; D001665:Binding Sites; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D008322:Mammals; D008958:Models, Molecular; D000075687:NEDD8 Protein; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D012097:Repressor Proteins / Q000378:metabolism*; D013379:Substrate Specificity; D020798:Two-Hybrid System Techniques; D025801:Ubiquitin / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; D014452:Ubiquitins; C092341:ATXN3 protein, human; D000067699:Ataxin-3