Biosynthesis of heparan sulfate – how regulated does it need to be?

Heparan sulfate proteoglycans (HSPGs) are ubiquitous in animals. The functional significance of the structural variability exhibited by the constituent HS chains remains a fundamental question in cell and developmental biology. The polysaccharides influence cell behaviour, by modulating the activities of signalling proteins or through interactions in the extracellular matrix. HS is synthesized as a linear polymer of alternating glucuronate (GlcA) and N ‐acetylglucosamine (GlcNAc) units. The resultant [GlcA‐GlcNAc] n polymer is partially modified through a series of N ‐deacetylation/ N ‐sulfation, GlcA C5‐epimerization and O ‐sulfation reactions (Esko & Lindahl 2001) and may be further modified by selective removal of O ‐sulfate groups (Ai et al . 2003). Owing to the variable extent of these reactions in different cells and tissues, and at different developmental stages, the mature HS products display different structures, typically expressed through sulfated domains of variable length and composition (Esko & Lindahl 2001; Casu & Lindahl 2001). These domains provide binding sites for protein ligands and thus constitute the structural basis for the diverse functional roles of HS. The regulated diversity of HS structure is demonstrated through compositional analysis of HS from various organs as well as by immunohistochemical recognition of HS epitopes (van Kuppevelt, T. H et al . 1998). So far, a precise structure–function relation has been defined only for the antithrombin‐binding pentasaccharide sequence (Casu & Lindahl 2001). HS is essential throughout development, as mouse embryos devoid of HS‐polymerizing enzymes fail in gastrulation (Gallagher 2001). By contrast, targeted disruption of genes encoding polymer‐modifying enzymes is associated with surprisingly mild phenotypes. Embryos lacking N ‐deacetylase/ N ‐sulfotransferase‐1, 2‐ O ‐sulfotransferase (Gallagher 2001) or GlcA C5‐epimerase (Li et al . 2003), thus show major defects incompatible with postnatal life, but also apparently normal organ systems known to rely on HS‐binding morphogens or growth factors for their development. Moreover, transgenic mice overexpressing heparanase appear essentially normal (Zcharia et al . 2004), in spite of an overall drastic reduction in HS chain size. How stringent are structure/function relations in HS–protein interactions?