A di-aromatic motif in the cytosolic tail of the mannose receptor mediatesendosomal sorting

The mannose receptor (MR), the prototype of a new family of multilectin rec eptor proteins important in innate immunity, undergoes rapid internalizatio n and recycling from the endosomal system back to the cell surface. Sorting of the MR in endosomes prevents the receptor from entering lysosomes where it would be degraded. Here, we focused on a diaromatic sequence (Tyr(18)-P he(19)) in the MR cytoplasmic tail as an endosomal sorting signal. The subc ellular distribution of chimeric constructs between the MR and the cation-d ependent mannose 6-phosphate receptor was assessed by Percoll density gradi ents and cell surface assays. Unlike the wild type constructs, mutant recep tors with alanine substitutions of Tyr(18)-Phe(19) were highly missorted to lysosomes, indicating that the di-aromatic motif of the MR cytoplasmic tai l mediates sorting in endosomes. Within this sequence Tyr(18) is the key re sidue with Phe(19) contributing to this function. Moreover, Tyr(18) was als o found to be essential for internalization, consistent with the presence o f overlapping signals for internalization and endosomal sorting in the cyto solic tail of the MR. A di-aromatic amino acid sequence in the cytosolic tail has now been shown to function in two receptors known to be internalized from the plasma membr ane, the MR and the cation-dependent mannose 6-phosphate receptor. This fea ture therefore appears to be a general determinant for endosomal sorting.