School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol, UK.
Centre for Cell Biology of Chronic Disease, Institute for Molecular Biosciences, The University of Queensland, SLCA, Australia.
Nat Commun. 2024 Aug 21;15(1):7180. doi: 10.1038/s41467-024-50971-0.
Commander is a multiprotein complex that orchestrates endosomal recycling of integral cargo proteins and is essential for normal development. While the structure of this complex has recently been described, how cargo proteins are selected for Commander-mediated recycling remains unclear. Here we identify the mechanism through which the unstructured carboxy-terminal tail of the cargo adaptor sorting nexin-17 (SNX17) directly binds to the Retriever sub-complex of Commander. SNX17 adopts an autoinhibited conformation where its carboxy-terminal tail occupies the cargo binding groove. Competitive cargo binding overcomes this autoinhibition, promoting SNX17 endosomal residency and the release of the tail for Retriever association. Furthermore, our study establishes the central importance of SNX17-Retriever association in the handover of integrin and lipoprotein receptor cargoes into pre-existing endosomal retrieval sub-domains. In describing the principal mechanism of cargo entry into the Commander recycling pathway we provide key insight into the function and regulation of this evolutionary conserved sorting pathway.
衔接蛋白复合物是一个多蛋白复合物，协调内体中整联蛋白货物蛋白的再循环，对正常发育至关重要。虽然该复合物的结构最近已经被描述，但货物蛋白如何被选择用于衔接蛋白复合物介导的再循环仍不清楚。在这里，我们确定了货物衔接蛋白分选连接蛋白 17（SNX17）无规则羧基末端尾巴直接与衔接蛋白复合物回收器亚基结合的机制。SNX17 采用自身抑制构象，其羧基末端尾巴占据货物结合槽。竞争性货物结合克服了这种自身抑制，促进 SNX17 进入内体并释放尾部与回收器结合。此外，我们的研究还确立了 SNX17-回收器结合在整合素和脂蛋白受体货物进入预先存在的内体回收子域中的核心重要性。在描述货物进入衔接蛋白复合物再循环途径的主要机制时，我们为该进化保守的分选途径的功能和调节提供了关键的见解。
