CONCEPTS AND PRINCIPLES OF O-LINKED GLYCOSYLATION

The biosynthesis, structures, and functions of O-glycosylation, as a c omplex posttranslational event, is reviewed and compared for the vario us types of O-glycans. Mucin-type O-glycosylation is initiated by tiss ue-specific addition of a GalNAc-residue to a serine or a threonine of the fully folded protein. This event is dependent on the primary, sec ondary, and tertiary structure of the glycoprotein. Further elongation and termination by specific transferases is highly regulated. We also describe some of the physical and biological properties that O-glycos ylation confers on the protein to which the sugars are attached. These include providing the basis for rigid conformations and for protein s tability. Clustering of O-glycans in Ser/Thr(/Pro)-rich domains allows glycan determinants such as sialyl Lewis X to be presented as multiva lent ligands, essential for functional recognition. An additional leve l of regulation, imposed by exon shuffling and alternative splicing of mRNA, results in the expression of proteins that differ only by the p resence or absence of Ser/Thr(/Pro)-rich domains. These domains may se rve as protease-resistant spacers in cell surface glycoproteins. Furth er biological roles for O-glycosylation discussed include the role of isolated mucin-type O-glycans in recognition events (e.g., during fert ilization and in the immune response) and in the modulation of the act ivity of enzymes and signaling molecules. In some cases, the O-linked oligosaccharides are necessary for glycoprotein expression and process ing. In contrast to the more common mucin-type O-glycosylation, some s pecific types of O-glycosylation, such as the O-linked attachment of f ucose and glucose, are sequon dependent. The reversible attachment of O-linked GlcNAc to cytoplasmic and nuclear proteins is thought to play a regulatory role in protein function. The recent development of nove l technologies for glycan analysis promises to yield new insights in t he factors that determine site occupancy, structure-function relations hip, and the contribution of O-linked sugars to physiological and path ological processes. These include diseases where one or more of the O- glycan processing enzymes are aberrantly regulated or deficient, such as HEMPAS and cancer.