Structural view of glycosaminoglycan-protein interactions

The essential role of protein-glycosaminoglycan interactions in the regulation of various physiological processes has been recognized for several decades but it is only recently that the molecular basis underlying such interactions has emerged. The different methodologies to elucidate the three-dimensional features of glycosaminoglycans along with the interactions with proteins cover high resolution NMR spectroscopy, X-ray crystallography, molecular modeling, and hydrodynamic measurements. The structural results that have accumulated have been organized in databases that allow rapid searching with entries related either to the type of glycosaminoglycan or the type of protein. Finally, three selected examples enlightening the complexity of the nature of the interactions occurring between proteins and glycosaminoglycans are given. The example of interactions between heparin and antithrombin III illustrates how such a complex mechanism as the regulation of blood coagulation by a specific pentasaccharide can be dissected through the combined use of dedicated carbohydrate chemistry and structural glycobiology. The second example deals with the study of complexes between chemokines and heparin, and shows how multimolecular complexes of proteins can be organized in space throughout the action of glycosaminoglycans. Again, the synthesis of chemical mimetics offers an unexpected route to the development of novel glycotherapeutics. Finally, the area of enzymes/glycosaminoglycans complexes is briefly covered to realize the limited knowledge that we have for such an important class of biomacromolecular complexes.