title: Atypical parkinsonism-associated retromer mutant alters endosomal sorting of specific cargo proteins.
abstract: The retromer complex acts as a scaffold for endosomal protein complexes that sort integral membrane proteins to various cellular destinations. The retromer complex is a heterotrimer of VPS29, VPS35, and VPS26. Two of these paralogues, VPS26A and VPS26B, are expressed in humans. Retromer dysfunction is associated with neurodegenerative disease, and recently, three VPS26A mutations (p.K93E, p.M112V, and p.K297X) were discovered to be associated with atypical parkinsonism. Here, we apply quantitative proteomics to provide a detailed description of the retromer interactome. By establishing a comparative proteomic methodology, we identify how this interactome is perturbed in atypical parkinsonism-associated VPS26A mutants. In particular, we describe a selective defect in the association of VPS26A (p.K297X) with the SNX27 cargo adaptor. By showing how a retromer mutant leads to altered endosomal sorting of specific PDZ ligand-containing cargo proteins, we reveal a new mechanism for perturbed endosomal cargo sorting in atypical parkinsonism.
authors.affiliation: School of Biochemistry, University of Bristol, Bristol BS8 1TD, England, UK.
authors.forename: Kirsty J
authors.initials: KJ
authors.lastname: McMillan
authors.affiliation: School of Biochemistry, University of Bristol, Bristol BS8 1TD, England, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gallon
authors.affiliation: School of Biochemistry, University of Bristol, Bristol BS8 1TD, England, UK.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Jellett
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Clairfeuille
authors.affiliation: School of Biochemistry, University of Bristol, Bristol BS8 1TD, England, UK.
authors.forename: Frances C
authors.initials: FC
authors.lastname: Tilley
authors.affiliation: School of Biochemistry, University of Bristol, Bristol BS8 1TD, England, UK.
authors.forename: Ian
authors.identifier: 0000-0002-4622-5358
authors.initials: I
authors.lastname: McGough
authors.affiliation: School of Biochemistry, University of Bristol, Bristol BS8 1TD, England, UK.
authors.forename: Chris M
authors.initials: CM
authors.lastname: Danson
authors.affiliation: Proteomics Facility, School of Biochemistry, University of Bristol, Bristol BS8 1TD, England, UK.
authors.forename: Kate J
authors.identifier: 0000-0002-5418-5392
authors.initials: KJ
authors.lastname: Heesom
authors.affiliation: School of Biochemistry, University of Bristol, Bristol BS8 1TD, England, UK.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Wilkinson
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Collins
authors.affiliation: School of Biochemistry, University of Bristol, Bristol BS8 1TD, England, UK pete.cullen@bristol.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Cullen
mesh_terms: D002460:Cell Line; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics*; D025941:Protein Interaction Mapping; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport; D058305:Sorting Nexins / Q000378:metabolism
chemical_list: D021122:Protein Subunits; C522885:SNX27 protein, human; D058305:Sorting Nexins