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Atypical parkinsonism-associated retromer mutant alters endosomal sorting of specific cargo proteins

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)389-399
Number of pages11
JournalJournal of Cell Biology
Volume214
Issue number4
DOIs
DateAccepted/In press - 12 Jul 2016
DatePublished (current) - 15 Aug 2016

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.

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via RU Press at http://jcb.rupress.org/content/214/4/389. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 487 KB, PDF document

    Licence: CC BY-NC-SA

  • Supplementary table PDF

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via RU Press at http://jcb.rupress.org/content/214/4/389. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 716 KB, PDF document

    Licence: CC BY-NC-SA

  • Figures and supplementary figure PDF

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via RU Press at http://jcb.rupress.org/content/214/4/389. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 53 MB, PDF document

    Licence: CC BY-NC-SA

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