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, tissuespecific, 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.

The nature of the conserved basic amino acid sequences found among 437 heparin binding proteins determined by network analysis

“…Heparan sulfate is a molecule that, in some manner, choreographs signalling pathways thereby allowing information to cross the cell membrane. 11,13 Heparin binding proteins play a key role in controlling development, for example, via the Wnt, Hedgehog, transforming growth factor-beta and fibroblast growth factor (FGF) pathways. 14 Furthermore, HS has been implicated in diseases such as Alzheimer's, 15 cancer 16 and sexually transmitted infections.…”

“…This statement is perhaps tautological, since almost all experimental investigations have involved the selection of proteins bound to HS/heparin via elution from a heparin column using salt that inherently selects for high charge interactions. 11 Ori et al 12 compiled a list of 435, nonredundant, human HS/heparin binding proteins (HEPbps) in the HS/heparin interactome, which include members of important protein families, such as growth factors, cytokines and morphogens. Heparan sulfate is a molecule that, in some manner, choreographs signalling pathways thereby allowing information to cross the cell membrane.…”

Investigating the relationship between temperature, conformation and calcium binding in heparin model oligosaccharides

“…The unusual conformational flexibility of the L-iduronate residue may contribute to this capability. However, it must be recalled that the present work deals with model oligosaccharides and might be expected to present subtly different properties to those pertaining in the polysaccharide [25].…”

Competence-induced protein Ccs4 facilitates pneumococcal invasion into brain tissue and virulence in meningitis

“…Streptococcus agalactiae penetrates the BBB via interactions between bacterial surface alpha C protein and host surface heparan sulfate chains [19]. It has been shown that heparan sulfate and heparin are defined by similar underlying backbones (GlcNAcα1-4GlcAβ1-4/IdoAα1-4) n , though heparin undergoes more extensive sulfation and uronic acid epimerization [20]. S. pneumoniae Ccs4 also contains an arginine-rich region (- R G R SA RR S RR E-).…”