title: An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis.
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.
authors.affiliation: Department of Neuroproteomics, Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Boeddrich
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gaumer
authors.forename: Annette
authors.initials: A
authors.lastname: Haacke
authors.forename: Nikolay
authors.initials: N
authors.lastname: Tzvetkov
authors.forename: Mario
authors.initials: M
authors.lastname: Albrecht
authors.forename: Bernd O
authors.initials: BO
authors.lastname: Evert
authors.forename: Eva C
authors.initials: EC
authors.lastname: Müller
authors.forename: Rudi
authors.initials: R
authors.lastname: Lurz
authors.forename: Peter
authors.initials: P
authors.lastname: Breuer
authors.forename: Nancy
authors.initials: N
authors.lastname: Schugardt
authors.forename: Stephanie
authors.initials: S
authors.lastname: Plassmann
authors.forename: Kexiang
authors.initials: K
authors.lastname: Xu
authors.forename: John M
authors.initials: JM
authors.lastname: Warrick
authors.forename: Jaana
authors.initials: J
authors.lastname: Suopanki
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wüllner
authors.forename: Ronald
authors.initials: R
authors.lastname: Frank
authors.forename: Ulrich F
authors.initials: UF
authors.lastname: Hartl
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
mesh_terms: D000251:Adenosine Triphosphatases; D000255:Adenosine Triphosphate / Q000378:metabolism; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000235:genetics*; D000067699:Ataxin-3; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004330:Drosophila / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D000071058:Huntingtin Protein; D002479:Inclusion Bodies / Q000378:metabolism; D008239:Lysine / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins; D017386:Sequence Homology, Amino Acid; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000255:Adenosine Triphosphate; D001120:Arginine; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; D008239:Lysine