Heparan sulfate proteoglycans - PubMed (original) (raw)

Heparan sulfate (HS) structure. HS biosynthesis initiates by the attachment of xylose to specific serine residues in HSPG core proteins followed by the formation of a linkage tetrasaccharide, glucuronic acid-galactose-galactose-xylose (GlcA-Gal-Gal-Xyl). Extl3 attaches the first _N_-acetyl-

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-glucosamine (GlcNAc) residue and an enzyme complex composed of Ext1 and Ext2 alternately adds GlcA and GlcNAc to the nascent chain. The chains simultaneously undergo a series of processing reactions that begins by the removal of the acetyl groups from clusters of GlcNAc residues and substitution of the free amino groups with sulfate, catalyzed by one or more _N_-deacetylase-_N_-sulfotransferases (Ndst). The C5 epimerase (HsGlce) epimerizes

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-glucuronic acids immediately adjacent to _N_-sulfoglucosamine units to

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-iduronic acid (IdoA). A series of _O_-sulfotransferases can then add sulfate: uronyl 2-_O_-sulfotransferase (Hs2st) adds sulfate at C2 of the iduronic acids (and less frequently to glucuronic acids), 6-_O_-sulfotransferases (Hs6st1-3) add sulfate at C6 of the N-sulfoglucosamine units and less frequently to _N_-acetylglucosamine, and 3-_O_-sulfotransferases (Hs3st1, 2, 3a, 3b, 4, 5, 6) add sulfate at C3 of glucosamine units (N-sulfated or N-unsubstituted). As shown in the top of the figure by red shading, the modifications occur in clusters of variable length (N-sulfated or NS domains), which are interspersed by unmodified domains (N-acetylated or NA domains). The regions at the junction of these domains are sometimes called NA/NS domains (not shown) because the extent of processing is less. The modified domains make up binding sites for protein ligands as depicted for antithrombin, FGF and FGF receptor. The HS chains can be further modified once they arrive at the cell surface or in the ECM by two endosulfatases (Sulf1 and Sulf2), which remove specific sulfate groups located at C6 of glucosamine units, or by the action of extracellular heparanase or extracellular proteases (not shown). (Figure adapted from Bishop et al. 2007; reprinted with permission from Nature Publishing Group © 2007.)