MOLECULAR-BASIS OF LYSOSOMAL-ENZYME RECOGNITION - 3-DIMENSIONAL STRUCTURE OF THE CATION-DEPENDENT MANNOSE 6-PHOSPHATE RECEPTOR

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-p hosphate receptor (IGF-II/CI-MPR). The two receptors, which share sequ ence similarities, constitute the P-type family of animal lectins. We now report the three-dimensional structure of a glycosylation-deficien t, yet fully functional form of the extracytoplasmic domain of the bov ine CD-MPR (residues 3-154) complexed with mannose 6-phosphate at 1.8 Angstrom resolution. The extracytoplasmic domain of the CD-MPR crystal lizes as a dimer, and each monomer folds into a nine-stranded flattene d beta barrel, which bears a striking resemblance to avidin. The dista nce of 40 Angstrom between the two ligand-binding sites of the dimer p rovides a structural basis for the observed differences in binding aff inity exhibited by the CD-MPR toward various lysosomal enzymes.