Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain.

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.
Mesh Terms:
Catalysis, Humans, Models, Molecular, Nerve Tissue Proteins, Nuclear Magnetic Resonance, Biomolecular, Nuclear Proteins, Protein Binding, Protein Structure, Quaternary, Protein Structure, Tertiary, Repressor Proteins, Ubiquitin
Proc. Natl. Acad. Sci. U.S.A.
Date: Sep. 06, 2005
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