Function and properties of chimeric MPR 46-MPR 300 mannose 6-phosphate receptors

The two known mannose 6-phosphate receptors (MPR 46 and MPR 300) mediate th e transport of mannose 6-phosphate-containing lysosomal proteins to lysosom es. Endocytosis of extracellular mannose g-phosphate ligands can only be me diated by MPR 300. Neither type of MPR appears to be sufficient for targett ing the full complement of lysosomal enzymes to lysosomes. The complements of lysosomal enzymes transported by either of the two receptors are distinc t but largely overlapping. Chimeric receptors were constructed in which the transmembrane and cytoplasmic domains of the two receptors were systematic ally exchanged. After expression of the chimeric receptors in cells lacking endogenous MPRs the binding of ligands, the subcellular distribution and t he sorting efficiency for lysosomal enzymes were analyzed. All chimeras wer e functional, and their subcellular distribution was similar to that of wil d type MPRs. The ability to endocytose lysosomal enzymes was restricted to receptors with the lumenal domain of MPR 300. The efficiency to sort lysoso mal enzymes correlated with the lumenal and cytoplasmic domains of MPR 300. In contrast to the wild type receptors, a significant fraction of most of the chimeric receptors was misrouted to lysosomes, indicating that the sign als determining the routing of MPRs have been fitted for the parent recepto r polypeptides.