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

Official URL:https://doi.org/10.1038/sj.emboj.7601043
PubMed:View item in PubMed
Creators Name:Boeddrich, A. and Gaumer, S. and Haacke, A. and Tzvetkov, N. and Albrecht, M. and Evert, B.O. and Mueller, E.C. and Lurz, R. and Breuer, P. and Schugardt, N. and Plassmann, S. and Xu, K. and Warrick, J.M. and Suopanki, J. and Wuellner, U. and Frank, R. and Hartl, U.F. and Bonini, N.M. and Wanker, E.E.
Journal Title:EMBO Journal
Journal Abbreviation:EMBO J
Volume:25
Number:7
Page Range:1547-1558
Date:5 April 2006
Keywords:Ataxin-3, VCP, Polyglutamine Aggregation, Animals
Abstract: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.
ISSN:0261-4189
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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