Proteomic identification and structural basis for the interaction between sorting nexin SNX17 and PDLIM family proteins

The sorting nexin SNX17 controls endosomal recycling of transmembrane cargo proteins including integrins, the amyloid precursor protein, and lipoprotein receptors. This requires association with the Commander trafficking complex and depends on the C terminus of SNX17 through unknown mechanisms. Using proteomics, we find that the SNX17 C terminus is sufficient for Commander interaction and also associates with members of the PDZ and LIM domain (PDLIM) family. SNX17 contains a type III PDZ binding motif that binds specifically to the PDLIM proteins. The structure of the PDLIM7 PDZ domain bound to the SNX17 C terminus reveals an unconventional perpendicular peptide interaction mediated by electrostatic contacts and a uniquely conserved proline-containing loop sequence in the PDLIM protein family. Our results define the mechanism of SNX17-PDLIM interaction and suggest that the PDLIM proteins may play a role in regulating the activity of SNX17 in conjunction with Commander and actin-rich endosomal trafficking domains. [Display omitted] •Sorting nexin SNX17 is essential for endosomal trafficking•Proteomics identifies PDLIM proteins and the Commander complex as interactors•Structure of PDLIM7 with SNX17 C terminus reveals a non-canonical PDZ interaction•PDLIM proteins may regulate SNX17 at actin-rich endosomal trafficking domains The SNX17 protein is critical for recycling many internalized transmembrane proteins from endosomes to avoid degradation in lysosomal compartments, but the mechanisms are poorly understood. Healy et al. provide new data linking SNX17 to the PDLIM family of actin-associated proteins and define the molecular principals of their highly specific interaction.