An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis
Arginine/lysine-rich motifs typically function as targeting signals for the translocation of proteins to the nucleus. In a new study, Annett Boeddrich (laboratory of Prof. Erich Wanker), Sebastian Gaumer, and colleagues found that in the polyglutamine protein ataxin-3 (Atx-3), such a canonical nuclear localization signal ( 282RKRR) serves as recognition site for interaction with the molecular chaperone VCP (TheEMBO Journal doi: 10.1038/ sj.emboj.7601043). Through this interaction, VCP modulates the fibrillogenesis of pathogenic forms of Atx-3 in a concentration-dependent manner. Low concentrations of VCP were found to stimulate Atx-3 fibrillogenesis while an excess of VCP suppressed it. No such effect was observed with a mutant Atx-3 protein as well as the polyglutamine protein, huntingtin, which both do not contain a functional VCP interaction motif. Interestingly, a stretch of four basic amino acids in the ubiquitin chain assembly factor E4B was also discovered to be important 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 but not of huntingtin. Together, these results define the VCP-Atx-3 association as a potential target for therapeutic intervention and suggest that an alteration of this interaction might influence the progression of spinocerebellar ataxia type 3.
Contact:
Pamela Cohen
p.cohen@mdc-berlin.de
+49 30 9406 2121
