NEDD8: a new ataxin-3 interactor.
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.
Ferro
Anabela
A
UnIGENe-IBMC, Instituto de Biologia Molecular e Celular, University of Porto, 4150-180 Porto, Portugal.
Carvalho
Ana Luísa
AL
Teixeira-Castro
Andreia
A
Almeida
Carla
C
Tomé
Ricardo J
RJ
Cortes
Luísa
L
Rodrigues
Ana-João
AJ
Logarinho
Elsa
E
Sequeiros
Jorge
J
Macedo-Ribeiro
Sandra
S
Maciel
Patrícia
P
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*
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