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Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2005 Sep 06; Vol. 102 (36), pp. 12700-5. Date of Electronic Publication: 2005 Aug 23. - Publication Year :
- 2005
-
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.
- Subjects :
- Ataxin-3
Catalysis
Humans
Models, Molecular
Nerve Tissue Proteins genetics
Nuclear Magnetic Resonance, Biomolecular
Nuclear Proteins
Protein Binding
Protein Structure, Quaternary
Protein Structure, Tertiary
Repressor Proteins
Nerve Tissue Proteins chemistry
Nerve Tissue Proteins metabolism
Ubiquitin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 102
- Issue :
- 36
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 16118278
- Full Text :
- https://doi.org/10.1073/pnas.0506344102