Atypical parkinsonism-associated retromer mutant alters endosomal sorting of specific cargo proteins
| Autor: | Frances C. Tilley, Chris M. Danson, Peter J. Cullen, Kate J. Heesom, Ian J. McGough, Adam P. Jellett, Matthew Gallon, Kirsty J McMillan, Kevin A. Wilkinson, Brett M. Collins, Thomas Clairfeuille |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
SNX27 Retromer Endosome Sorting Nexins Endosomes Biology Cell Line 03 medical and health sciences VPS35 Parkinsonian Disorders Report Protein Interaction Mapping Humans VPS26A Research Articles Cell Biology Cell biology Retromer complex Protein Subunits Protein Transport 030104 developmental biology VPS29 Mutation |
| Zdroj: | The Journal of Cell Biology McMillan, K J, Gallon, M J, Jellett, A P, Clairfeuille, T, Tilley, F C, McGough, I, Danson, C M, Heesom, K J, Wilkinson, K A, Collins, B M & Cullen, P J 2016, ' Atypical parkinsonism-associated retromer mutant alters endosomal sorting of specific cargo proteins ', Journal of Cell Biology, vol. 214, no. 4, pp. 389-399 . https://doi.org/10.1083/jcb.201604057 |
| ISSN: | 1540-8140 |
| DOI: | 10.1083/jcb.201604057 |
| Popis: | Mutations in the retromer complex, which is involved in sorting integral membrane proteins from endosomes to cellular compartments, are associated with atypical parkinsonism, but how these mutations affect retromer function remains unclear. Through a quantitative proteomic analysis of the retromer interactome, McMillan et al. reveal a new mechanism for perturbed endosomal sorting in parkinsonism. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|