Structure and contribution to the heparin cofactor II-mediated inhibition of thrombin of naturally oversulphated sequences of dermatan sulphate

Abstract

Dermatan sulphate (DS) obtained from bovine and pig mucosa and pig skin, and charge-enriched fractions of a selected DS preparation, were characterized in terms of charge density, M(r) and disaccharide composition of chondroitin ABC lyase digests, and by 13C-n.m.r. spectroscopy. Besides the major IdoA-GalNAc4SO3 sequences, all DS preparations contain about 10% disulphated disaccharide sequences (mostly IdoA2SO3-GalNAc4SO3, with minor amounts of IdoA-GalNAc4,6SO3). DS fragments (prepared by radical-catalysed depolymerization of DS and retaining the internal structure of the parent polysaccharide) as well as Smith degraded fragments [SD-DS, obtained by controlled degradation of periodate-oxidized and borohydride-reduced DS (RO-DS)] with the general structure GalNAc4SO3(IdoA2SO3-GalNAc4SO3)n-R (where R is the remnant of a glycol-split uronic acid, and n = 2-3 and 3-4) were characterized by one- and two-dimensional 1H-n.m.r., 13C-n.m.r. and disaccharide composition analysis. In accordance with previous findings [Maimone and Tollefsen (1990) J. Biol. Chem. 265, 18263-18271], only fragments with n > or = 3 significantly enhance the heparin cofactor II-mediated inhibition of thrombin. In natural DS preparations and their fractions, this activity (as well as the antithrombotic activity in an animal model) appears to require IdoA2SO3-containing sequences. The heparin cofactor II activity of DS, RO-DS and SD-DS fragments decreases with decreasing M(r). However, RO-DS fragments are more active than DS fragments of similar M(r), probably because of the extra flexibility endowed by glycol-split IdoA residues.

Hepatocyte Growth Factor/Scatter Factor Binds with High Affinity to Dermatan Sulfate

“…(22). Only in the specific case of heparin cofactor II has a comparable high affinity interaction with DS been demonstrated, and this is dependent upon the presence of a specific, highly sulfated DS oligosaccharide sequence (23,24).In the present study, we demonstrate that HGF/SF also binds to DS with high affinity. This gives further insight into the specific structural requirements for oligosaccharide binding to HGF/SF.…”

Dermatan sulfate activates nuclear factor-κb and induces endothelial and circulating intercellular adhesion molecule-1

“…Several reports have shown that heparan sulfate is necessary for the function of heparin-binding ligands, such as members of the fibroblast growth factor (FGF) family (9,10). Dermatan sulfate (DS) GAGs have also been found to bind heparin-binding growth factors, including FGF-2 (4), hepatocyte growth factor/scatter factor (11), heparin cofactor-II (12,13), platelet factor-4 (14), fibronectin (15), and protein C inhibitor (16). In human wounds, DS contributes the majority of FGF-2-dependent cell responsiveness, with heparan sulfate having lesser activity (4).…”

Dermatan Sulfate Binds and Potentiates Activity of Keratinocyte Growth Factor (FGF-7)

“…Wound fluid-derived DS, as well as physiologic concentrations of commercially purified DS, has been shown to promote FGF-2 function (1). DS and DS proteoglycans also bind to and influence the activity of other heparin-and HS-binding proteins including hepatocyte growth factor/scatter factor (2), thrombin (3), heparin cofactor II (4,5), fibronectin (6), platelet factor-4 (7), regulated on activation normal T cell expressed and secreted (RANTES) (8), and interferon-␥ (9, 10). Thus, although less well understood, DS-protein interactions are likely to be important events in control of several cellular behaviors.…”