Fig. 8: Model of SNX17-Commander association and its regulation through ØxNxx[Y/F] cargo-density sensing and endosomal sub-domain organization.

SNX17 associates with the endosomal membrane enriched for phosphatidylinositol 3-monophosphate (PI3P). We hypothesize that endosomal localization is enhanced through the binding of transmembrane cargoes containing ØxNxx[Y/F] sorting motifs. With increasing cargo density, the auto-inhibitory conformation defined by the SNX17 tail associating with the cargo binding groove in the FERM domain of SNX17 is displaced, enabling the presentation of SNX17 carboxy-tail to the conserved VPS26C:VPS35L interface. The direct binding of cargo-bound SNX17 to Retriever ultimately leads to Commander-mediated recycling of cargo back to the plasma membrane. For simplicity, other endosomal sorting complexes, such as the F-actin polymerizing WASH complex, ESCPE-1 and Retromer are not shown.