Heparan sulfate proteoglycans at a glance.

Proteoglycans are abundant components of the cell surface and extracellular matrix that mediate critical interactions between cells and their environment. They play a variety of biological roles in normal tissues and in response to injury and disease. Proteoglycans regulate the distribution of extracellular signaling molecules such as morphogens and chemokines, and modulate signaling events at the cell surface that influence cell fate determination, proliferation, adhesion and motility. Secreted proteoglycans can also serve as structural constituents of the matrix, whereas cell surface proteoglycans may participate in endocytosis and vesicular trafficking, regulating the movement of molecules between intracellular and extracellular compartments. Proteoglycans consist of a core protein carrying long unbranched disaccharide chains. Different types of chain are distinguished by the nature of the repeating disaccharides; heparan sulfate (HS) contains alternating N-acetyl glucosamine (GlcNAc) and glucuronic or iduronic acid residues. Heparan sulfate proteoglycans (HSPGs) carry one or more HS chains, and can be grouped into three distinct classes: the syndecans, which have a single transmembrane domain; the glypicans, which are linked to the outer plasma membrane by a glycosylphosphatidylinositol (GPI) anchor; and a varied group of secreted proteoglycans, including perlecan, agrin and collagen XVIII. HS chains are attached at specific serine residues on the core proteins through a tetrasaccharide linker. Following chain initiation, HS is synthesized by glycosyltransferases of the exostosin (EXT) family. Initially the chains contain only GlcNAc and glucuronic acid, but following chain elongation, additional modifications take place: GlcNAc N-deacetylase/ N-sulfotransferase (NDST) converts Nacetyl groups in some regions to Nsulfates, C5 epimerase modifies nearby glucuronic acid residues to iduronic acid and specific sulfotransferases introduce additional sulfate groups (see Esko and Selleck, 2002; Kramer and Yost, 2003; Bulow and Hobert, 2006). These modification reactions do not go to completion, which leads to enormous structural variety in HS chains. This diversity allows HSPGs to bind to a wide range of proteins and influence many biological processes.