Overview of HS synthesis and modification of HSPGs. (A) HS chain initiation begins with the sequential attachment of a core tetra-saccharide sequence to the serine residue of the HSPG. HS synthesis enzymes then facilitate the attachment of repeating GlcA-GlcNAc disaccharide moieties, creating a linear HS chain, whereas multiple HS-modifying enzymes alter the linear HS chain through distinct modifications of specific residues (including O-sulfation, N-sulfation, and epimerization). This sequential process produces a unique chain of modified HS attached to the core HSPG. Extracellular modification of HS also occurs through the removal of sulfates by sulf enzymes, as well as the removal of sections of the HS chain by heparanase. (B) Overview of the main HSPG subcategories, including syndecans, transmembrane proteins that contain a variable (V) domain, as well as 2 common domains (C1 and C2), of which C2 contains a PDZ binding motif, glypicans, which are glycophosphatidylinositol–linked proteins; and secreted or pericellular proteins such as perlecan and agrin. The cell membrane lipid bilayer is shown in black, and pink delineates the core HSPG protein with attached HS chains (in green) and chondroitin sulfate chains (in blue).