Atypical parkinsonism-associated retromer mutant alters endosomal sorting of specific cargo proteins.
Atypical parkinsonism-associated retromer mutant alters endosomal sorting of specific cargo proteins.
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DOI：
10.1083/jcb.201604057
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发表时间：
2016-08-15
期刊：
影响因子：
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通讯作者：
Cullen PJ
中科院分区：
文献类型：
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作者：
McMillan KJ;Gallon M;Jellett AP;Clairfeuille T;Tilley FC;McGough I;Danson CM;Heesom KJ;Wilkinson KA;Collins BM;Cullen PJ
逆转录酶复合物中的突变，参与将整合的膜蛋白从内体分类到细胞区室，与非典型帕金森病相关，但这些突变如何影响逆转录酶功能仍不清楚。通过对逆转录相互作用组的定量蛋白质组学分析，McMillan等人揭示了帕金森病中干扰内体分选的新机制。逆转录复合物作为内体蛋白复合物的支架，将整合的膜蛋白分类到各种细胞目的地。逆转录复合物是VPS29、VPS35和VPS26的异源三聚体。这些旁系同源物中的两个，VPS26 A和VPS26 B，在人类中表达。Retromer功能障碍与神经退行性疾病相关，最近发现三种VPS26A突变（p.K93E、p.M112V和p.K297X）与非典型帕金森综合征相关。在这里，我们应用定量蛋白质组学提供了一个详细的描述retromer相互作用。通过建立比较蛋白质组学方法，我们确定了这种相互作用是如何在非典型帕金森病相关的VPS26A突变体的扰动。特别地，我们描述了VPS26A（p.K297X）与SNX27货物衔接子的关联中的选择性缺陷。通过展示一个retromer突变体如何导致改变特定的PDZ配体的货物蛋白的内体分选，我们揭示了一个新的机制扰动内体货物分选在非典型帕金森氏症。
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.