Structural basis for Retriever-SNX17 assembly and endosomal sorting.
Structural basis for Retriever-SNX17 assembly and endosomal sorting.
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Retriever-SNX17 组装和内体分选的结构基础。
DOI：
10.1101/2024.03.12.584676
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Chen,Baoyu
中科院分区：
文献类型：
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作者：
Singla,Amika;Boesch,DanielJ;JoyceFung,HoYee;Ngoka,Chigozie;Enriquez,AveryS;Song,Ran;Kramer,DanielA;Han,Yan;Juneja,Puneet;Billadeau,DanielD;Bai,Xiaochen;Chen,Zhe;Turer,EmreE;Burstein,Ezra;Chen,Baoyu
在内体循环过程中，分类连接蛋白17 （SNX17）通过将许多膜货物蛋白拴在retriver复合体上来促进它们的运输。尽管它很重要，但这种相互作用的机制仍然难以捉摸。在这里，我们提供了snx17 -寻回犬相互作用的生化、结构、细胞和蛋白质组学分析。我们的数据显示，SNX17在基本状态下采用自抑制构象，其FERM结构域隔离其c端尾部。货物蛋白与FERM结构域的结合通过直接竞争取代了c端尾部。低温电子显微镜（cro - em）显示，释放的尾巴通过结合VPS35L和VPS26C亚基之间的高度保守界面与寻回犬接合。破坏该界面会损害寻回者- snx17的相互作用，随后影响snx17依赖性货物的再循环并改变质膜蛋白质组的组成。有趣的是，snx17在retriver上的结合口袋可以被其他含有一致酸性c末端尾基序的配体利用。总之，我们的发现揭示了内体运输关键货物蛋白的机制，并揭示了猎犬如何潜在地与其他调节因子结合或被病原体利用。
During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we provide biochemical, structural, cellular, and proteomic analyses of the SNX17-Retriever interaction. Our data reveal that SNX17 adopts an autoinhibited conformation in the basal state, with its FERM domain sequestering its C-terminal tail. The binding of cargo proteins to the FERM domain displaces the C-terminal tail through direct competition. The released tail engages with Retriever by binding to a highly conserved interface between its VPS35L and VPS26C subunits, as revealed by cryogenic electron microscopy (cryo-EM). Disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargoes and altering the composition of the plasma membrane proteome. Intriguingly, the SNX17-binding pocket on Retriever can be utilized by other ligands containing a consensus acidic C-terminal tail motif. Together, our findings uncover a mechanism underlying endosomal trafficking of critical cargo proteins and reveal how Retriever can potentially engage with other regulatory factors or be exploited by pathogens.