Interactions between heparan sulfate and proteins-design and functional implications.

Heparan sulfate (HS) proteoglycans at cell surfaces and in the extracellular matrix of most animal tissues are essential in development and homeostasis, and variously implicated in disease processes. Functions of HS polysaccharide chains depend on ionic interactions with a variety of proteins including growth factors and their receptors. Negatively charged sulfate and carboxylate groups are arranged in various types of domains, generated through strictly regulated biosynthetic reactions and with enormous potential for structural variability. The level of specificity of HS-protein interactions is assessed through binding experiments in vitro using saccharides of defined composition, signaling assays in cell culture, and targeted disruption of genes for biosynthetic enzymes followed by phenotype analysis. While some protein ligands appear to require strictly defined HS structure, others bind to variable saccharide domains without any apparent dependence on distinct saccharide sequence. These findings raise intriguing questions concerning the functional significance of regulation in HS biosynthesis.