Heparan sulfate and heparin interactions with proteins

Abstract

Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissue-specific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro, ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. The properties that have been thought to bestow protein binding and biological activity upon HS and heparin vary from high levels of sequence specificity to a dependence on charge. In contrast to these opposing opinions, we will argue that the evidence supports both a level of redundancy and a degree of selectivity in the structure-activity relationship. The relationship between this apparent redundancy, the multi-dentate nature of heparin and HS polysaccharide chains, their involvement in protein networks and the multiple binding sites on proteins, each possessing different properties, will also be considered. Finally, the role of cations in modulating HS/heparin activity will be reviewed and some of the implications for structure-activity relationships and regulation will be discussed.

Keywords: cations; heparan sulfate; heparin; polysaccharide; protein binding; redundancy.

Figure 1.

Structural features of HS and heparin. (a) Possible substitution patterns in heparin/HS. (b) The major disaccharide unit of heparin, which corresponds typically to 70–80% [1], although differences between sources, such as porcine mucosa and bovine lung are typical [2]. (c) The major repeating disaccharide unit of HS from, for example, porcine mucosa. Considerable variation in HS composition also occurs between species and tissues [–5]. ϕ (phi) and ψ (psi) denote glycosidic linkage torsion angles.

Figure 2.

Protein–protein interaction (PPI) network of heparin/HS binding proteins. (a) PPI network for AT. (b) PPI network for FGF-1. Networks were generated with STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) [112]. They are shown in the confidence view. Stronger associations are represented by thicker lines.