Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.
Department of Bioinformatics & Systems Biology, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
PLoS Biol. 2020 Mar 9;18(3):e3000631. doi: 10.1371/journal.pbio.3000631. eCollection 2020 Mar.
Endocytic recycling of internalized transmembrane proteins is essential for many important physiological processes. Recent studies have revealed that retromer-related Sorting Nexin family (SNX)-Bin/Amphiphysin/Rvs (BAR) proteins can directly recognize cargoes like cation-independent mannose 6-phosphate receptor (CI-MPR) and Insulin-like growth factor 1 receptor (IGF1R); however, it remains poorly understood how SNX-BARs select specific cargo proteins and whether they recognize additional ligands. Here, we discovered that the binding between SNX-BARs and CI-MPR or IGF1R is mediated by the phox-homology (PX) domain of SNX5 or SNX6 and a bipartite motif, termed SNX-BAR-binding motif (SBM), in the cargoes. Using this motif, we identified over 70 putative SNX-BAR ligands, many of which play critical roles in apoptosis, cell adhesion, signal transduction, or metabolite homeostasis. Remarkably, SNX-BARs could cooperate with both SNX27 and retromer in the recycling of ligands encompassing the SBM, PDZ-binding motif, or both motifs. Overall, our studies establish that SNX-BARs function as a direct cargo-selecting module for a large set of transmembrane proteins transiting the endosome, in addition to their roles in phospholipid recognition and biogenesis of tubular structures.
内吞的跨膜蛋白的内体再循环对于许多重要的生理过程是必不可少的。最近的研究表明，与 retromer 相关的分选衔接蛋白家族（SNX）-Bin/Amphiphysin/Rvs（BAR）蛋白可以直接识别货物，如阳离子非依赖性甘露糖 6-磷酸受体（CI-MPR）和胰岛素样生长因子 1 受体（IGF1R）；然而，SNX-BAR 如何选择特定的货物蛋白，以及它们是否识别其他配体，仍知之甚少。在这里，我们发现 SNX-BAR 与 CI-MPR 或 IGF1R 的结合是由 SNX5 或 SNX6 的 phox 同源（PX）结构域和货物中的二肽基 motif（称为 SNX-BAR 结合 motif（SBM））介导的。利用这个 motif，我们鉴定了超过 70 个潜在的 SNX-BAR 配体，其中许多在细胞凋亡、细胞黏附、信号转导或代谢物稳态中发挥关键作用。值得注意的是，SNX-BARs 可以与 SNX27 和 retromer 一起在包含 SBM、PDZ 结合 motif 或这两个 motif 的配体的循环中合作。总的来说，我们的研究确立了 SNX-BARs 作为一组跨膜蛋白的直接货物选择模块，这些蛋白通过内体转运，除了它们在磷脂识别和管状结构的生物发生中的作用之外。
