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  • The EMBO Journal (2006) 25, 1547 - 1558
  • doi:10.1038/sj.emboj.7601043

Published online: 9 March 2006

An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis

Annett Boeddrich1,8, Sébastien Gaumer2,8,9, Annette Haacke3, Nikolay Tzvetkov3, Mario Albrecht4, Bernd O Evert5, Eva C Müller1, Rudi Lurz6, Peter Breuer3, Nancy Schugardt1, Stephanie Plas zligmann1, Kexiang Xu2, John M Warrick2, Jaana Suopanki1, Ullrich Wüllner5, Ronald Frank7,10, Ulrich F Hartl3,10, Nancy M Bonini2,10 and Erich E Wanker1,10

  1. Department of Neuroproteomics, Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany
  2. Department of Biology, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA, USA
  3. Max-Planck-Institute for Biochemistry, Martinsried, Germany
  4. Max-Planck-Institute for Informatics, Saarbrücken, Germany
  5. Department of Neurology, University of Bonn, Bonn, Germany
  6. Max-Planck-Institute for Molecular Genetics, Berlin, Germany
  7. Department of Chemical Biology, GBF, Braunschweig, Germany
  8. These two authors contributed equally to this work
  9. Present address: Universite de Versailles Saint-Quentin-en-Yvelines, 45 avenue des Etats-Unis, F-78035 Versailles cedex, France
  10. These are senior authors

Correspondence to:

Erich E Wanker, Department of Neuroproteomics, Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Stras zlige 10, 13092 Berlin, Germany. Tel.: +49 30 9406 2157; Fax: +49 30 9406 2552; E-mail: ewanker@mdc-berlin.de

Received 28 September 2005; Accepted 21 February 2006

Arginine/lysine-rich motifs typically function as targeting signals for the translocation of proteins to the nucleus. Here, we demonstrate that such a motif consisting of four basic amino acids in the polyglutamine protein ataxin-3 (Atx-3) serves as a recognition site for the interaction with the molecular chaperone VCP. Through this interaction, VCP modulates the fibrillogenesis of pathogenic forms of Atx-3 in a concentration-dependent manner, with low concentrations of VCP stimulating fibrillogenesis and excess concentrations suppressing it. No such effect was observed with a mutant Atx-3 variant, which does not contain a functional VCP interaction motif. Strikingly, a stretch of four basic amino acids in the ubiquitin chain assembly factor E4B was also discovered to be critical for VCP binding, indicating that arginine/lysine-rich motifs might be generally utilized by VCP for the targeting of proteins. In vivo studies with Drosophila models confirmed that VCP selectively modulates aggregation and neurotoxicity induced by pathogenic Atx-3. Together, these results define the VCP–Atx-3 association as a potential target for therapeutic intervention and suggest that it might influence the progression of spinocerebellar ataxia type 3.

  • Keywords:

    • ataxin-3,
    • VCP,
    • polyglutamine aggregation