Multiple sorting motifs direct the transport of membrane proteins within the endocytic pathway. Those required for transport from the trans-Golgi network (TGN) to endosomes have been well characterized. Now, Matthew Seaman reports that a novel conserved sorting motif – Trp/Phe-Leu-Met/Val – is needed for retromer-mediated endosome-to-TGN transport of proteins that cycle between these two compartments (see ). Retromer is a multiprotein complex required for retrieval back to the Golgi of proteins such as the cation-independent mannose 6-phosphate receptor (CIMPR), which mediates sorting of lysosomal hydrolases. Seaman uses CD8 fusion proteins carrying parts of the cytoplasmic tail of the CIMPR to identify which region is required for endosome-to-Golgi transport and for the interaction with retromer. Then, using alanine substitution, he shows that the tri-peptide motif (Trp-Leu-Met) is essential for both processes. Retromer-mediated endosome-to-Golgi retrieval of sortilin, he reports, requires a biochemically similar motif (Phe-Leu-Val). The identification of this conserved motif, he suggests, begins to explain how retromer functions in endosome-to-
