Capturing the Conformational Ensemble of the Mixed Folded Polyglutamine Protein Ataxin-3.

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 101087697 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-4186 (Electronic) Linking ISSN: 09692126 NLM ISO Abbreviation: Structure Subsets: MEDLINE
    • Publication Information:
      Publication: 2000- : Cambridge, Mass. : Cell Press
      Original Publication: London : Current Biology, c1993-
    • Subject Terms:
      Protein Folding*; Ataxin-3/*chemistry ; Machado-Joseph Disease/*genetics; Ataxin-3/genetics ; Humans ; Molecular Dynamics Simulation ; Mutation ; Peptides/chemistry ; Peptides/genetics ; Protein Conformation
    • Abstract:
      Ataxin-3 is a deubiquitinase involved in protein quality control and other essential cellular functions. It preferentially interacts with polyubiquitin chains of four or more units attached to proteins delivered to the ubiquitin-proteasome system. Ataxin-3 is composed of an N-terminal Josephin domain and a flexible C terminus that contains two or three ubiquitin-interacting motifs (UIMs) and a polyglutamine tract, which, when expanded beyond a threshold, leads to protein aggregation and misfolding and causes spinocerebellar ataxia type 3. The high-resolution structure of the Josephin domain is available, but the structural and dynamical heterogeneity of ataxin-3 has so far hindered the structural description of the full-length protein. Here, we characterize non-expanded and expanded variants of ataxin-3 in terms of conformational ensembles adopted by the proteins in solution by jointly using experimental data from nuclear magnetic resonance and small-angle X-ray scattering with coarse-grained simulations. Our results pave the way to a molecular understanding of polyubiquitin recognition.
      Competing Interests: Declaration of Interests The authors declare absence of any conflict of interest.
      (Copyright © 2020 Elsevier Ltd. All rights reserved.)
    • Grant Information:
      FC001029 United Kingdom Wellcome Trust; FC001029 United Kingdom CRUK_ Cancer Research UK; MC_U117533887 United Kingdom MRC_ Medical Research Council; MC_PC_13054 United Kingdom MRC_ Medical Research Council; FC001029 United Kingdom MRC_ Medical Research Council
    • Contributed Indexing:
      Keywords: Monte Carlo simulations; NMR; PRE; SAXS; ensemble refinement; hybrid methods; intrinsically unfolded proteins; neurodegeneration; polyglutamine
    • Accession Number:
      0 (Peptides)
      26700-71-0 (polyglutamine)
      EC 3.4.19.12 (Ataxin-3)
    • Publication Date:
      Date Created: 20201016 Date Completed: 20211123 Latest Revision: 20220129
    • Publication Date:
      20240105
    • Accession Number:
      10.1016/j.str.2020.09.010
    • Accession Number:
      33065068