Oligosaccharides as Recognition Molecules – A coming of age

Abstract

Most membrane and secreted proteins as well as lysosomal acid hydrolases contain covalently‐linked oligosaccharides that exhibit a vast array of structures. We now recognize that these oligosaccharides participate in numerous biologic processes ranging from folding of nascent glycoproteins to trafficking of lymphocytes in the circulation. The requirement for proper glycosylation is underscored by the growing list of human diseases that result from defects in glycan assembly.Our early work focused on the structural analysis of Asn‐linked glycans and their biosynthesis. We then turned to the study of a specific glycosylation event that serves to target acid hydrolases to lysosomes, i.e. the formation of mannose 6‐ phosphate residues on the Asn‐linked glycans of these enzymes. We have investigated the unique two‐step pathway for the biosynthesis of this marker and explored how the first enzyme in this process distinguishes acid hydrolases from non‐lysosomal glycoproteins, a critical step in the sorting process. This led to studies of the two Man‐6‐P receptors that bind the Man‐6‐P determinant and deliver the hydrolases to lysosomes. This pathway serves as a valuable model for studies of intracellular protein trafficking. Analysis of mouse models of lysosomal storage disorders caused by the failure to synthesize the Man‐6‐P recognition marker is providing insight into the pathophysiology of these disorders.