The N-terminal carbohydrate recognition site of the cation-independent mannose 6-phosphate receptor

The 300-kDa cation-independent mannose 6-phosphate receptor (CI-MPR) plays a critical role in the trafficking of newly synthesized mannose 6-phosphate-containing acid hydrolases to the lysosome. The receptor contains two high affinity carbohydrate recognition sites within its 15-domain extracytoplasmic region, with essential residues for carbohydrate recognition located in domain 3 and domain 9. Previous studies have shown that these two sites are distinct with respect to carbohydrate specificity. In addition, expression of truncated forms of the CI-MPR demonstrated that domain 9 can be expressed as an isolated domain, retaining high affinity (K-d similar to 1 nM) carbohydrate binding, whereas expression of domain 3 alone resulted in a protein capable of only low affinity binding (K-d similar to 1 muM) toward a lysosomal enzyme. In the current report the crystal structure of the N-terminal 432 residues of the CI-MPR, encompassing domains 1-3, was solved in the presence of bound mannose 6-phosphate. The structure reveals the unique architecture of this carbohydrate binding pocket and provides insight into the ability of this site to recognize a variety of mannose-containing sugars.