P‐Type Lectins and Lysosomal Enzyme Trafficking

Abstract

The P-type lectins derived their name from their ability to bind phosphorylated mannose residues. There are only two members of this lectin family: the 300 kDa cation-independent mannose 6-phosphate receptor (CI-MPR) and the 46 kDa cation-dependent mannose 6-phosphate receptor (CD-MPR), both of which are involved in targeting newly synthesized soluble acid hydrolases to the lysosome. Lysosomal enzymes acquire mannose 6-phosphate (Man-6-P) residues on their Nlinked oligosaccharides which function as a recognition marker for the MPRs. The MPRs are found ubiquitously in higher eukaryotes, and most cell types express both receptors. The CI-MPR is often referred to as the mannose 6-phosphate/ insulin-like growth factor 11 receptor to reflect the bifunctional nature of the mammalian receptor which is capable of binding Man-6-P-containing ligands as well as the polypeptide hormone, insulin-like growth factor I1 (IGF-11). However, recent studies showing that the CI-MPR binds two other ligands, retinoic acid [ 11 and the urokinase-type plasminogen activator receptor [2], demonstrate that the CI-MPR is truly a multifunctional receptor capable of recognizing a number of different ligands via distinct binding sites.In addition to soluble lysosomal enzymes, Man-6-P residues have been identified on a number of other proteins, including epidermal growth factor receptor, Herpes simplex virus glycoprotein D, thyroglobulin, transforming growth factor-p precursor, proliferin, leukemia inhibitory factor, and DNase I. The ability of these proteins to be recognized by the MPRs suggests that the receptors are involved in a number of diverse cellular events due to their carbohydrate binding activities. This Chapter will focus on the carbohydrate binding specificities of the MPRs and will summarize the information gained from the recent crystal structure of the CD-MPR which has provided the first look at the carbohydrate-recognition domain (CRD) of this lectin family. The reader is referred to reviews [3, 41 for a more complete summary of earlier work on the biosynthesis and intracellular trafficking of the MPRs and lysosomal enzymes. Carbohydrates in Chemistry and Biology