GAG binding proteins

Proteins interacting with GAG chains are not limited to growth and morphogenic factors. GAG chains on proteoglycans also bind to extracellular proteins like collagens and contribute to the organization of the extracellular matrix. Several serum proteins involved in lipid metabolism are also binding to GAG chains. In this context, the group of Jeff Esko has clearly demonstrated the role of heparan sulfate proteoglycans in the hepatic clearance of triglyceride-rich lipoproteins. The binding to GAG chains affects in some cases the activity of the interacting proteins. For example, the protease activity of antithrombin III is increased by 1’000-fold after binding to heparin. GAG chains are also relevant in infectious diseases as they are sometimes used as receptor by pathogens like the herpes simplex virus 1 and 2. 

FIG: CLASSES OF GAG-BINDING PROTEINS

The complex patterns of sulfation along GAG chains build up a series of binding motifs for multiple proteins. The mapping of these motifs is a difficult task and too few examples have been characterized in detail. Some of these motifs are sulfated disaccharides, whereas others like the FGF binding domains are sulfated hexasaccharides.

FIG: LIST OF GAG MOTIFS BINDING SITES

The interaction of bioactive proteins with GAG chains in the vicinity of receptors is often represented schematically, because little structural evidence is available. In the case of FGF and their receptors, dimers of the ligand and of the receptor interact with a single heparan sulfate chain. The analysis of the crystal structure of a complex comprising two FGF1 units, two FGF receptor-2 units and a heparin chain revealed that both FGF units and one FGF receptor unit directly bind to the GAG chain.

FIG: FGF2 RECEPTOR BINDING

The crystal structure of the FGF1-FGF receptor-heparin complex shows that the binding to the GAG chain is asymmetrical, meaning that the complex is likely to assemble stepwise. Although other examples of ligand-receptor-GAG interactions have not been documented at high resolution, it is reasonable to assume that such interactions would be similar to the FGF1 instance.