Heparan sulfate

Heparan sulfate chains occur on several types of proteoglycans, which are mainly found on basement membranes and secreted in the extracellular matrix. Membrane-bound proteoglycans are either anchored in the cell membrane through a transmembrane domain, as for example the family of syndecans, or through glycosylphosphatidylinositol as found for glypicans. Most of these proteoglycans carry only one to three heparan sulfate chains. The large proteoglycan perlecan is secreted into the extracellular matrix of blood vessels, where it is essential to maintain the barrier function of endothelial cells.

The glycosylation and sulfation pattern of heparan sulfate chains changes according to the localization and activation status of the carrier cells. For example, heparan sulfate chains on syndecan-2 are important in mediating left-right asymmetry in the developing Xenopus embryo. The work of Joseph Yost has shown that the migration of mesoderm is controlled by variable glyco-sulfation patterns in syndecan-2 expressed on ectodermal cells. Accordingly, treatment of embryos with heparanase leads to randomized location of asymmetrical organs, such as heart and gut.

FIG: HS TABLE

Although heparan sulfates and heparin are both sulfated carbohydrates structures, they are structurally and functionally distinct. Heparin is a potent anticoagulant produced by mast cells where it is stored in secretory granules. The degree of sulfation and GlcA epimerization is higher in heparin than in heparan sulfates, which increases the binding to antithrombin-III and thereby the anticoagulant effect. Heparan sulfate are produced by nearly all cell types and display only little anticoagulant activity.

FIG: COMPARING HS and HEPARIN

GAG chains like heparan sulfates are important for the formation of protein gradients involved in the control of organ growth and development. The essential contribution of GAG is underlined by the study of mutations in Drosophila that affect the biosynthesis of heparan sulfate. Nearly all genes involved in heparan sulfate formation, including the PAPS transporter, EXT glycosyltransferases, sulfotransferases, UDP-GlcA decarboxylase and UDP-Glc dehydrogenase have been implied in shaping morphogenic gradients in the developing Drosophila embryo. Such morphogenic gradients enable the formation of polarized structures, providing cues for the positioning and activation of cells during development. Morphogenic and growth factors such as FGFs, BMPs, wingless (Wg/Wnt), and hedgehog (Hh) bind to heparan sulfate chains, thereby increasing their local concentration and extending their range across tissues and structures. As discussed in the context of exostoses, defects in heparan sulfates disrupt gradients and lead to aberrant cell migration and proliferation.