title: VCP binding influences intracellular distribution of the slow Wallerian degeneration protein, Wld(S).
abstract: Wallerian degeneration slow (Wld(S)) mice express a chimeric protein that delays axonal degeneration. The N-terminal domain (N70), which is essential for axonal protection in vivo, binds valosin-containing protein (VCP) and targets both Wld(S) and VCP to discrete nuclear foci. We characterized the formation, composition and localization of these potentially important foci. Missense mutations show that the N-terminal sixteen residues (N16) of Wld(S) are essential for both VCP binding and targeting Wld(S) to nuclear foci. Removing N16 abolishes foci, and VCP binding sequences from ataxin-3 or HrdI restore them. In vitro, these puncta co-localize with proteasome subunits. In vivo, Wld(S) assumes a range of nuclear distribution patterns, including puncta, and its neuronal expression and intranuclear distribution is region-specific and varies between spontaneous and transgenic Wld(S) models. We conclude that VCP influences Wld(S) intracellular distribution, and thus potentially its function, by binding within the N70 domain required for axon protection.
authors.affiliation: The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Wilbrey
authors.forename: Jane E
authors.initials: JE
authors.lastname: Haley
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wishart
authors.forename: Laura
authors.initials: L
authors.lastname: Conforti
authors.forename: Giacomo
authors.initials: G
authors.lastname: Morreale
authors.forename: Bogdan
authors.initials: B
authors.lastname: Beirowski
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Babetto
authors.forename: Robert
authors.initials: R
authors.lastname: Adalbert
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
authors.forename: Trevor
authors.initials: T
authors.lastname: Smith
authors.forename: David J A
authors.initials: DJ
authors.lastname: Wyllie
authors.forename: Richard R
authors.initials: RR
authors.lastname: Ribchester
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coleman
mesh_terms: D000251:Adenosine Triphosphatases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001923:Brain Chemistry / Q000235:genetics; D018797:Cell Cycle Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007424:Intracellular Fluid / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D000074405:Valosin Containing Protein; D014855:Wallerian Degeneration / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; C442580:Wld protein, mouse; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse; C000614180:Vcp protein, rat