The specificity of interactions between proteins and sulfated polysaccharides

Abstract

Sulfated polysaccharides are capable of binding with proteins at several levels of specifi city. As highly acidic macromolecules, they can bind non-specifi cally to any basic patch on a protein surface at low ionic strength, and such interactions are not likely to be physiologically signifi cant. On the other hand, several systems have been identifi ed in which very specifi c substructures of sulfated polysaccharides confer high affi nity for particular proteins; the best-known example of this is the pentasaccharide in heparin with high affi nity for antithrombin, but other examples may be taken from the study of marine invertebrates: the importance of the fi ne structure of dermatan sulfate (DS) to its interaction with heparin cofactor II (HCII), and the involvement of sea urchin egg-jelly fucans in species specifi c fertilization. A third, intermediate, kind of specifi c interaction is described for the cell-surface glycosaminoglycan heparan sulfate (HS), in which patterns of sulfate substitution can show differential affi nities for cytokines, growth factors, and morphogens at cell surfaces and in the intracellular matrix. This complex interplay of proteins and glycans is capable of influencing the diffusion of such proteins through tissue, as well as modulating cellular responses to them.

Application of drug discovery software to the identification of heparin-binding sites on protein surfaces: a computational survey of the 4-helix cytokines

“…Their receptors are however closely related, and shared subunits are common: for example the gp130 receptor subunit shared by several of the long-chain cytokines (such as Il-6 and LIF) and Detailed analysis of the predicted binding sites has been avoided as being premature in the absence of experimental data. Though these molecular modelling exercises offer no more than informed predictions, they are in agreement with all the experimental data so far in failing to identify any single amino acid sequence motif or feature of secondary structure common to all heparin binding sites [15,26,48]. The significance and function (if any) of the capacity of cytokines to bind heparin or heparan sulfate cannot be generalised; each case requires separate investigation.…”

“…2 Residues containing atoms within 3.5 Å of ligand in the 5 lowest energy complexes ... [1] ... [3] Page 17 of 34 http://mc.manuscriptcentral.com/tandf/jenmol 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 2 Residues containing atoms within 3.5 Å of ligand in the 5 lowest energy complexes Table 3: Prediction of heparin binding to the interferon/IL10 group of 4-helical cytokines. ... [7] ... [19] ... [15] ... [20] ... [18] ... [17] ... [21] ... [5] ... [22] ... [6] ... [16] ... [13] ... [24] ... [8] ... [25] ... [23] ... [14] ... [26] ... [9] ... [27] ... …”

“…Heparan sulfate is often represented, and imagined, in terms of sequences, rather than three-dimensional structures [15]. The crystal structure of FGF-1 (2axm.pdb) complexed with a heparin oligosaccharide (Fig.…”

Roles of Cellular Activation and Sulfated Glycans inHaemophilus somnusAdherence to Bovine Brain Microvascular Endothelial Cells

“…Although structurally similar to the heparan sulfate expressed on cell surfaces, it is important to note that heparin has a higher number of sulfate groups that in turn give it a high-density negative charge. This negative charge will, in turn, interact with any protein containing a region of highly positive charges (31). Thus, heparin is a somewhat nonspecific inhibitor of highly charged physical interactions.…”

Sulfated polymannuroguluronate inhibits Tat-induced SLK cell adhesion via a novel binding site, a KKR spatial triad

“…Sugar-protein interactions are predominantly dependent on saccharide composition and the extent and distribution of sulfation of the sugar backbone [25,26] . SPMG is a heparin-like sulfated polysaccharide and is rich in 1, 4-linked β-D-mannuronate.…”