Recruitment of the endosomal WASH complex is mediated by the extended 'tail' of Fam21 binding to the retromer protein Vps35
Recruitment of the endosomal WASH complex is mediated by the extended 'tail' of Fam21 binding to the retromer protein Vps35
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DOI：
10.1042/bj20111761
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发表时间：
2012-02-15
影响因子：
4.1
通讯作者：
Seaman, Matthew N. J.
中科院分区：
文献类型：
--
作者：
Harbour, Michael E.;Breusegem, Sophia Y.;Seaman, Matthew N. J.
逆转录复合体是一种保守的内体蛋白分选复合体，它将膜蛋白分选到新生的内体小管中。膜蛋白的识别是由GRAIL选择性逆转录复合体介导的，它是VPS35(空泡蛋白分类35)、Vps29和Vps26蛋白的稳定三聚体。我们最近报道了货物选择性逆转聚体复合体与Wiskott-Aldrich综合征同源复合体相关，Wiskott-Aldrich综合征同源复合体是一种多聚体蛋白复合体，调节内小体的小管动力学。在本研究中，我们证明了逆转录-WASH复合体的相互作用是通过WASH复合体-FAM21蛋白与VPS35结合的长的非结构‘尾’结构域发生的，这一相互作用是必要的，也是充分的，可以将WASH复合体靶向内小体。FAM21-Tail还与FKBP15(FK506结合蛋白15)结合，FKBP15是一种与溃疡性结肠炎相关的蛋白质，介导FKBP15的膜结合。上调的Fam21-Tail表达抑制了WASH复合体与逆转录聚体的结合，导致细胞质WASH复合体的增加。此外，Fam21-Tail的过表达会导致细胞铺展缺陷，这意味着WASH复合体在调节膜到内小体到细胞表面通路的动员方面具有活性。
The retromer complex is a conserved endosomal protein sorting complex that sorts membrane proteins into nascent endosomal tubules. The recognition of membrane proteins is mediated by the cargo-selective retromer complex, a stable trimer of the Vps35 (vacuolar protein sorting 35), Vps29 and Vps26 proteins. We have recently reported that the cargo-selective retromer complex associates with the WASH (Wiskott-Aldrich syndrome homologue) complex, a multimeric protein complex that regulates tubule dynamics at endosomes. In the present study, we show that the retromer-WASH complex interaction occurs through the long unstructured 'tail' domain of the WASH complex-Fam21 protein binding to Vps35, an interaction that is necessary and sufficient to target the WASH complex to endosomes. The Fam21-tail also binds to FKBP15 (FK506-binding protein 15), a protein associated with ulcerative colitis, to mediate the membrane association of FKBP15. Elevated Fam21-tail expression inhibits the association of the WASH complex with retromer, resulting in increased cytoplasmic WASH complex. Additionally, overexpression of the Fam21-tail results in cells-preading defects, implicating the activity of the WASH complex in regulating the mobilization of membrane into the endosome-to-cell surface pathway.