J. Clin. Invest. 108: 169–173 (2001). DOI: 10.1172/JCI200113530. terms of disaccharide composition; the disaccharides are distinguished by the presence of variably sulfated or nonsulfated GlcA/IdoA and GlcN residues. Generally, the same set of disaccharides exists in most tissues, but their relative content varies quantitatively. For example, the disaccharide GlcA-GlcNS3S occurs predominantly in endothelial cells and connective tissue mast cells, as this unit is a critical substructure in the pentasaccharide sequence that binds antithrombin (13, 14). In contrast, kidney HS contains a large amount of IdoA2SGlcNS3S, but the precise function of this unit in ligand binding is not known (15). Interestingly, the basic structural disaccharides of HS appear to be quite ancient.

Another way to characterize structure is in terms of the relative distribution of the major N-substituents of the GlcN residues: tracts of contiguous N-acetylated disaccharide units (NA domains), contiguous N-sulfated sequences of variable length (NS domains), and alternating N-acetylated and N-sulfated units (NA/NS domains)(Figure 1). Such N-substitution patterns appear to be characteristic of the cells/tissues from which the HS was obtained. Notably, heparin, the mast cell polysaccharide, may be considered essentially a single, unusually extended NS domain. Since other modifications, such as O-sulfation and epimerization of GlcA to L-IdoA, depend on prior N-sulfation of GlcN units, the modified disaccharide units tend to cluster in the NS or NA/NS domains (16). The disaccharide composition and the arrangement of NA and NS domains do not by themselves define binding sites for specific ligands. Instead, binding occurs to specific sets of variably modified disaccharides usually within the NS or NA/NS domains (17, 18). The beststudied example to date is the “lock-and-key” interaction between HS/heparin and antithrombin, which leads to inactivation of thrombin, factor Xa, and other serine proteinases of the coagulation cascade. This interaction depends on a very specific structure of a pentasaccharide that contains a central 3-O-sulfated GlcN residue (Glc-NAc6SGlcAGlcNS3S6SIdoA2SGlcNS6S)(see Figure 1, bottom)(13). Other examples are the interactions of glycoprotein gD from Herpes simplex virus (see Shukla and Spear, this Perspective series, ref. 19) with an oligosaccharide containing IdoA2S-GlcN3S and of FGF-1 and FGF-2 with N-sulfated pentasaccharide sequences containing IdoA2S and GlcN6S units in distinct combinations (see Gallagher, this series, ref. 20; and ref. 21). The distribution of binding sites for other ligands and their corresponding oligosaccharide sequences are less clearcut. Recent studies have focused on sequences that mediate binding and/or activation of PDGF, platelet factor 4, HGF (scatter factor), lipoprotein lipase, Herpes simplex glycoprotein gC, laminin, and chemokines. Some of the binding sites involve discontinuous domains of the chains (eg, IFN-γ, platelet factor 4, and IL-8)(see ref. 16 for relevant references). In other cases, the chain may act as a template, approximating a ligand with its binding partner (13, 22, 23). The expression of binding sites occurs in a tissue-specific manner and can change during development, aging, and disease. An unexplored question concerns the potential variation of structure in a given tissue in different individuals of the same species that might arise from differences in nutrition or genetic background.