2AGA

De-ubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain

Summary for 2AGA

• Entry DOI: 10.2210/pdb2aga/pdb
• NMR Information: BMRB: 6742
• Descriptor: Machado-Joseph disease protein 1 (1 entity in total)
• Functional Keywords: polyglutamine, ubiquitin, uim, ataxia, vcp/p97, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 21820.61

Authors

Mao, Y.,Senic-Matuglia, F.,Di Fiore, P.,Polo, S.,Hodsdon, M.E.,De Camilli, P. (deposition date: 2005-07-26, release date: 2005-08-30, Last modification date: 2024-05-08)

Primary citation

Mao, Y.,Senic-Matuglia, F.,Di Fiore, P.P.,Polo, S.,Hodsdon, M.E.,De Camilli, P.
Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain.
Proc.Natl.Acad.Sci.Usa, 102:12700-12705, 2005

PubMed 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.

PubMed: 16118278
DOI: 10.1073/pnas.0506344102

Experimental method

SOLUTION NMR