NEDD8: a new ataxin-3 interactor

• Autor(a) principal: Ferro, Anabela
• Data de Publicação: 2007
• Outros Autores: Carvalho, Ana Luísa, Castro, Andreia Cristiana Teixeira, Almeida, Carla, Tomé, Ricardo J., Cortes, Luísa, Rodrigues, Ana João, Santos, Elsa Clara Carvalho Logarinho, Sequeiros, Jorge, Maciel, P.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/1822/67703
• topic: Animals; Ataxin-3; Binding sites; HeLa cells; Humans; Hydrolysis; Mammals; Models, Molecular; NEDD8 protein; Nerve tissue proteins; Nuclear proteins; Protein binding; Protein transport; Repressor proteins; Substrate specificity; Two-Hybrid system techniques; Ubiquitin; Polyglutamine; UBL; E3 ligase; Neurodegeneration; MJD/SCA3; Science & Technology

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.