Involvement of sugars in protein¯protein interactions

In a cell there is an intricate machinery involved in the biosynthesis of complex oligosaccharides of glycoproteins, glycolipids, and proteoglycans. These oligosaccharides play important roles in several biological processes, including the folding and transport of glycoproteins across cellular compartments. Defective glycan synthesis has been shown to have serious pathological consequences and result in several human diseases. The oligosaccharide moieties bind to cellular proteins with high specificity and modulate the homoand hetero-dimerization of glycoproteins. Owing to the conformational flexibility of oligosaccharides, the torsional angles of a disaccharide unit, particularly around the 1-6linkage, adjust in such a way that the side groups of the oligosaccharides orient themselves in a manner that promotes favorable interactions with the binding residues of the protein. Branched oligosaccharides cross-link proteins and generate infinite networks of protein¯carbohydrate complexes, resulting in the modulation of various cell responses. Glycosaminoglycans, the oligosaccharide moieties of proteoglycans, bind growth factors with a high degree of specificity and induce interactions with growth factor receptors, thereby regulating their biological activity. Using an experimental model system to study the sugar mediated protein¯protein interactions, we are investigating the sugar ligand-dependent interactions between alpha-Lactalbumin (alpha-LA) and beta-1,4-galactosyltransferase (beta4Gal-T). Also, using a molecular modeling method, we are investigating the heparin dependent dimerization of fibroblast growth factor and growth factor receptor. Our results, together with studies from various other laboratories, support the hypothesis that in the oligosaccharide induced recognition process, sugars accelerate the assembly of the complex by positioning and orienting the molecules in an optimal fashion that brings about specific protein¯protein or protein¯carbohydrate interactions.