Structure-activity relationship of heparan sulphate.

HS influences fundamental cellular properties and biochemical processes at the cell surface. In addition to the issues already discussed, it has a profound effect on cell adhesion and migration through its interaction with many extracellular matrix proteins, most notably fibronectin and thrombospondin; it is closely linked to lipid metabolism through its capacity to bind low-density lipoprotein and lipoprotein lipase; and aberrations in HS structure and degradation are linked to human malignancy and Alzheimer's disease [26,27]. The subtle variations in HS structure enable it to distinguish between families of related proteins such as the FGFs, the chemokines [28] and the TGF beta s [29]. The multifunctional nature of HS is the result of its structural diversity and strategic positioning in the pericellular domain. The biosynthesis of HS, in common with other complex carbohydrates, is not directed by any known template yet the system is clearly subject to quite precise control so that in general, the HS family has a common domain organization that is finely tuned at the cellular level to produce HS species of variable length, fine structure and biological properties. A major challenge for future research will be to unravel the regulatory mechanisms that determine the molecular structure of HS. It remains unclear whether these mechanisms are entirely intrinsic in nature or subject to substantial modulation by the cellular microenvironment.