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 i...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 36; pp. 12700 - 12705
Main Authors Mao, Yuxin, Senic-Matuglia, Francesca, Di Fiore, Pier Paolo, Polo, Simona, Hodsdon, Michael E., De Camilli, Pietro
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 06.09.2005
National Acad Sciences
Subjects
Active sites
Ataxin-3
Biological Sciences
Catalysis
Catalytic activity
Chemical equilibrium
Enzymes
Humans
Machado Joseph disease
Models, Molecular
Mutation
Nerve Tissue Proteins - chemistry
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurodegenerative diseases
Neurological disorders
NMR
Nuclear magnetic resonance
Nuclear Magnetic Resonance, Biomolecular
Nuclear Proteins
Protein Binding
Protein Structure, Quaternary
Protein Structure, Tertiary
Proteins
Repressor Proteins
Structural analysis
Ubiquitin - metabolism
Ubiquitins
Western blotting
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Summary: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.
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Abbreviations: JD, Josephin domain; NOE, nuclear Overhauser effect; polyQ, polyglutamine; Ub, ubiquitin; UIM, Ub-interacting motif; VCP, valosin-containing protein.
Contributed by Pietro De Camilli, July 25, 2005
Author contributions: Y.M., F.S.-M., P.P.D.F., S.P., M.E.H., and P.D.C. designed research; Y.M., F.S.-M., S.P., and M.E.H. performed research; F.S.-M. and S.P. contributed new reagents/analytic tools; Y.M., F.S.-M., P.P.D.F., S.P., M.E.H., and P.D.C. analyzed data; and Y.M., M.E.H., and P.D.C. wrote the paper.
To whom correspondence may be addressed. E-mail: michael.hodsdon@yale.edu or pietro.decamilli@yale.edu.
Data deposition: The JD chemical shift assignments have been deposited in the BioMagRes-Bank (BMRB accession no. 6742). Coordinates for the ensemble of the JD structures have been deposited in the Protein Data Bank (PDB ID code 2AGA).
Note. Shortly before submission, an independent solution structure of the ataxin-3 JD was published in PNAS (43). Comparison to the structure presented here reveals striking similarities in overall global conformation, with one significant and interesting difference involving a large rotation in the orientation of α3 relative to α2. Both studies found evidence for structural mobility of α3, which is consistent with the observation of variable conformations.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0506344102