Department of Cell Biology, Yale School of Medicine, New Haven, CT 06520.
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):267-72. doi: 10.1073/pnas.1316482111. Epub 2013 Dec 16.
Retromer is an evolutionarily conserved protein complex composed of the VPS26, VPS29, and VPS35 proteins that selects and packages cargo proteins into transport carriers that export cargo from the endosome. The mechanisms by which retromer is recruited to the endosome and captures cargo are unknown. We show that membrane recruitment of retromer is mediated by bivalent recognition of an effector of PI3K, SNX3, and the RAB7A GTPase, by the VPS35 retromer subunit. These bivalent interactions prime retromer to capture integral membrane cargo, which enhances membrane association of retromer and initiates cargo sorting. The role of RAB7A is severely impaired by a mutation, K157N, that causes Charcot-Marie-Tooth neuropathy 2B. The results elucidate minimal requirements for retromer assembly on the endosome membrane and reveal how PI3K and RAB signaling are coupled to initiate retromer-mediated cargo export.
回转体(retromer)是一种进化上保守的蛋白复合物，由 VPS26、VPS29 和 VPS35 蛋白组成，它选择并将货物蛋白包装到运输载体中，从内体(exosome)中输出货物。回转体被招募到内体并捕获货物的机制尚不清楚。我们发现，通过 VPS35 回转体亚基对 PI3K 效应物 SNX3 和 RAB7A GTPase 的二价识别，来介导回转体的膜募集。这些二价相互作用使回转体准备捕获完整的膜货物，从而增强了回转体的膜结合，并启动货物分拣。RAB7A 的作用因导致 2B 型腓骨肌萎缩症的突变 K157N 而严重受损。这些结果阐明了在内体膜上组装回转体的最小要求，并揭示了 PI3K 和 RAB 信号如何偶联以启动回转体介导的货物输出。
