Review Article

Aberrant Glycosylation as Biomarker for Cancer: Focus on CD43

Figure 1

Schematic representation of N-glycosylation process. N-Glycosylation is an evolutionary conserved stepwise process that can be summarized as follows. (a) The assembling of the precursor oligosaccharide occurs at the cytoplasmic side of endoplasmic reticulum (ER) and starts with dolichol-pyrophosphate (Dol-PP), which is a nucleotide linked to a monosaccharide on a lipid carrier, an isoprenoid compound (90–100 carbon atoms total). The sequential incorporation of monosaccharides N-acetyl-glucosamine (GlcNAc) and Mannose (Man) is catalyzed by various glycosyltransferases. Once the intermediate Dol-PP-GlcNA2cMan5 is made, it flips to the luminal side of the ER, where four further residues of mannose and three residues of glucose (Glc) are added, leading to Dol-PP-GlcNAc2Man9Glc3. (b) When the proteins containing the consensus sequence for N-glycosylation (Asn-X-Ser and Asn-X-Thr) translocate to the ER, they are glycosylated by the oligosaccharyltransferase (OST) that catalyzes the transfer of the N-glycan to specific asparagine residues included within the consensus sequence (Asn-X-Ser/Thr) of the target proteins. After the oligosaccharide is transferred to the target protein, specific enzymes remove the three Glucose residues and one particular Mannose. The ER lumen contains a specific glycosyltransferase that binds to target protein, catalyzing the addition of Glucose residues only when the target protein is unfolded or misfolded. The newly glycosylated Glc1GlcNAc2Man7−9 oligosaccharides are then bound by two specific lectins, the ER-membrane-attached Calnexin or ER-luminal Calreticulin, which will allow the glycoprotein folding. Once folding is completed, the glucose residue is removed. (c) N-Glycosylated proteins move from ER to Golgi, where specific enzymes catalyse their sequential modifications to the Man8(GlcNAc)2 chains. In particular, in the cis-Golgi compartment, most Mannose residues of the original backbone chain are removed, leading to a N-glycan core structure constituted by GlcNAc2Man3. In mammals, two main groups of oligosaccharides linked to proteins are found: complex N-glycans and high-Mannose N-glycans. These structures are generated during the passage of the proteins toward the trans-side by the subsequent addition of Mannose residues (for the high-mannose N-glycans) and by addition of three residues of N-acetyl glucosamine (GlcNAc), two residues of Gal (galactose), two residues of NeuAc (N-acetylneuraminic acid) or sialic acid, and a single fucose residue (for the complex N-glycans). (d) Graphic legend of described structures.
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