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| Subject Categories: Proteins | Molecular Biology of Disease |
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| The EMBO Journal
(2006) 25, 1547–1558, doi:10.1038/sj.emboj.7601043 Published online 9 March 2006 |
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| An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis |
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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 Pla mann1, 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
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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 To whom correspondence should be addressed Erich E Wanker, Department of Neuroproteomics, Max Delbrueck Center for Molecular Medicine (MDC), Robert-Roessle-Stra e 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; Published online 9 March 2006. |
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| Abstract |
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| 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. |
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| Keywords: ataxin-3, VCP, polyglutamine aggregation |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHConformational changes in the AAA ATPase p97?p47 adaptor complex The EMBO Journal Article (03 May 2006) Nature Genetics Letter (01 Apr 2004) Nature Structural Biology Article (01 Oct 2003) |
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