Abstract
Proteoglycans (PGs) are glycosylated proteins of biological importance at cell surfaces, in the extracellular matrix, and in the circulation. PGs are produced and modified by glycosaminoglycan (GAG) chains in the secretory pathway of animal cells. The most common GAG attachment site is a serine residue followed by a glycine (-ser-gly-), from which a linker tetrasaccharide extends and may continue as a heparan sulfate, a heparin, a chondroitin sulfate, or a dermatan sulfate GAG chain. Which type of GAG chain becomes attached to the linker tetrasaccharide is influenced by the structure of the protein core, modifications occurring to the linker tetrasaccharide itself, and the biochemical environment of the Golgi apparatus, where GAG polymerization and modification by sulfation and epimerization take place. The same cell type may produce different GAG chains that vary, depending on the extent of epimerization and sulfation. However, it is not known to what extent these differences are caused by compartmental segregation of protein cores en route through the secretory pathway or by differential recruitment of modifying enzymes during synthesis of different PGs. The topic of this review is how different aspects of protein structure, cellular biochemistry, and compartmentalization may influence GAG synthesis.
Highlights
Proteoglycans (PGs) are glycosylated proteins of biological importance at cell surfaces, in the extracellular matrix, and in the circulation
The acidic sugars are hexuronic acids that alternate with amino sugars in repeated disaccharide units: glucuronic acid (GlcA), that may become iduronic acid (IdoA) upon C5 epimerization, which occurs in certain GAG domains during heparan sulfate (HS) and heparin synthesis, and in the conversion of chondroitin sulfate (CS) into dermatan sulfate (DS)
It is well established that motifs in the PG protein cores influence the structure of the GAG chains that are attached to their potential modification sites
Summary
Proteoglycans (PGs) consist of a protein core that, during transport through the secretory pathway, acquires one or more usually negatively charged glycosaminoglycan (GAG) chains. Certain patterns of epimerization and sulfation along GAG chains promote ionic interactions with growth factors and other signaling molecules, regulating growth development and differentiation and influencing immunological mechanisms The discovery of such mechanisms has increased the interest in PGs in what concerns cancer development, metastasis, and therapy regimes [6,7]. One suggested mechanism is through sulfation and phosphorylation of sugar units of a linker tetrasaccharide that attaches GAG chains to a modification site of a protein core. In the former cases (HS/heparin), the amino sugar is N-acetyl-glucosamine (GlcNAc), while in the latter cases (CS/DS) it is N-acetylgalactosamine (GalNAc) In all these cases the amino sugars alternate with GlcA in an enzyme-catalyzed polymerization process resulting in long, linear GAG chains, consisting of disaccharide units that may undergo extensive modification.
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