The oligosaccharides attached to glycoproteins serve various functions. For example, some proteins require N-linked oligosaccharides in order to fold properly in the ER. This function has been demonstrated in studies with the antibiotic tunicamycin, which blocks the first step in the formation of the dolichol-linked oligosaccharide precursor and therefore inhibits synthesis of all N-linked oligosaccharides in cells (see Figure 13-17, top left). For example, in the presence of tunicamycin, the influenza virus hemagglutinin precursor polypeptide (HA₀) is synthesized, but it cannot fold properly and form a normal trimer; in this case, the protein remains, misfolded, in the rough ER. Moreover, mutation of a particular asparagine in the hemagglutinin sequence to a glutamine residue prevents addition of an N-linked oligosaccharide to that site and causes the protein to accumulate in the ER in an unfolded state.

In addition to promoting proper folding, N-linked oligosaccharides confer stability on many secreted glycoproteins. Many secretory proteins fold properly and are transported to their final destination even if the addition of all N-linked oligosaccharides is blocked, for example, by treatment with tunicamycin. However, such nonglycosylated proteins have been shown to be less stable than their glycosylated forms. For instance, glycosylated fibronectin, a normal component of the extracellular matrix, is degraded much more slowly by tissue proteases than is nonglycosylated fibronectin.

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Oligosaccharides on certain cell-surface glycoproteins also play a role in cell-cell adhesion. For example, the plasma membrane of white blood cells (leukocytes) contains cell-adhesion molecules (CAMs) that are extensively glycosylated. The oligosaccharides in these molecules interact with a sugar-binding domain in certain other CAMs found on endothelial cells lining blood vessels. This interaction tethers the leukocytes to the endothelium and assists in their movement into tissues during an inflammatory response to infection (see Figure 20-40). Other cell-surface glycoproteins possess oligosaccharide side chains that can induce an immune response. A common example is the ABO blood group antigens, which are O-linked oligosaccharides attached to glycoproteins and glycolipids on the surfaces of erythrocytes and other cell types (see Figure 7-20). In both cases, oligosaccharides are added to the luminal face of these membrane proteins, in a manner similar to what is shown in Figure 13-18 for soluble proteins. The luminal face of these membrane proteins is topologically equivalent to the exterior face of the plasma membrane, where these proteins eventually end up.