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An arginine/lysine‐rich motif is crucial for VCP/p97‐mediated modulation of ataxin‐3 fibrillogenesis
Author(s) -
Boeddrich Annett,
Gaumer Sébastien,
Haacke Annette,
Tzvetkov Nikolay,
Albrecht Mario,
Evert Bernd O,
Müller Eva C,
Lurz Rudi,
Breuer Peter,
Schugardt Nancy,
Plaßmann Stephanie,
Xu Kexiang,
Warrick John M,
Suopanki Jaana,
Wüllner Ullrich,
Frank Ronald,
Hartl Ulrich F,
Bonini Nancy M,
Wanker Erich E
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601043
Subject(s) - fibrillogenesis , arginine , biology , lysine , microbiology and biotechnology , biochemistry , amino acid , mutant , ubiquitin , plasma protein binding , protein folding , fibril , gene
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.