title: Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain.
abstract: Spinocerebellar ataxia type 3 is a human neurodegenerative disease resulting from polyglutamine tract expansion. The affected protein, ataxin-3, which contains an N-terminal Josephin domain followed by tandem ubiquitin (Ub)-interacting motifs (UIMs) and a polyglutamine stretch, has been implicated in the function of the Ub proteasome system. NMR-based structural analysis has now revealed that the Josephin domain binds Ub and has a papain-like fold that is reminiscent of that of other deubiquitinases, despite primary sequence divergence but consistent with its deubiqutinating activity. Mutation of the catalytic Cys enhances the stability of a complex between ataxin-3 and polyubiquitinated proteins. This effect depends on the integrity of the UIM region, suggesting that the UIMs are bound to the substrate polyubiquitin during catalysis. We propose that ataxin-3 functions as a polyubiquitin chain-editing enzyme.
authors.affiliation: Howard Hughes Medical Institute and Department of Cell Biology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Mao
authors.forename: Francesca
authors.initials: F
authors.lastname: Senic-Matuglia
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Di Fiore
authors.forename: Simona
authors.initials: S
authors.lastname: Polo
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hodsdon
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D000067699:Ataxin-3; D002384:Catalysis; D006801:Humans; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019906:Nuclear Magnetic Resonance, Biomolecular; D009687:Nuclear Proteins; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D025801:Ubiquitin; C092341:ATXN3 protein, human; D000067699:Ataxin-3