Molecular basis of lysosomal enzyme recognition: Three-dimensional structure of the cation-dependent mannose 6-phosphate receptor

Abstract

Targeting of newly synthesized lysosomal hydrolases to the lysosome is mediated by the cation-dependent mannose 6-phosphate receptor (CD-MPR) and the insulin-like growth factor II/cation-independent mannose 6-phosphate receptor (IGF-II/CI-MPR). The two receptors, which share sequence similarities, constitute the P-type family of animal lectins. We now report the three-dimensional structure of a glycosylation-deficient, yet fully functional form of the extracytoplasmic domain of the bovine CD-MPR (residues 3-154) complexed with mannose 6-phosphate at 1.8 Å resolution. The extracytoplasmic domain of the CD-MPR crystallizes as a dimer, and each monomer folds into a nine-stranded flattened β barrel, which bears a striking resemblance to avidin. The distance of 40 Å between the two ligand- binding sites of the dimer provides a structural basis for the observed differences in binding affinity exhibited by the CD-MPR toward various lysosomal enzymes.