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

Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12700-5. doi: 10.1073/pnas.0506344102. Epub 2005 Aug 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Ataxin-3
  • Catalysis
  • Humans
  • Models, Molecular
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Magnetic Resonance, Biomolecular
  • Nuclear Proteins
  • Protein Binding
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • Repressor Proteins
  • Ubiquitin / metabolism*

Substances

  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • Ubiquitin
  • ATXN3 protein, human
  • Ataxin-3

Associated data

  • PDB/2AGA