Glycobiology: 'the function of sugar in the IgG molecule'

Immunoglobulin G (IgG) is glycosylated in both the Fc and the Fab regions of the protein with a heterogeneous ensemble of structures (glycoforms) that is both highly reproducible (i.e. nonrandom) and site specific. In normal IgG, the 2 highly conserved oligosaccharides of the Fc region are found buried between the CH2 domains, forming specific protein-saccharide interactions with the Fc protein surface. One of the functions attributed to the Fc oligosaccharides of normal IgG is to maintain the conformational arrangements of the Fc domains as well as the hinge regions. These structural features are necessary for Fc effector functions such as Clq and monocyte binding. A hallmark of rheumatoid arthritis (RA) patients is a dramatic increase in the presence of serum IgG containing Fc oligosaccharides lacking an outer arm galactose residue (termed 'G0' glycoforms). The increased level of G0 has been shown to be directly related to the pathogenesis of RA. Nuclear magnetic resonance relaxation studies of the Fc region from normal and RA IgG, as well as examination of x-ray structures, show that the G0 oligosaccharides have an increased mobility resulting from the loss of binding between the G0 oligosaccharide and the Fc protein surface. From these observations it follows that regions of the protein surface that are normally covered by the oligosaccharide are revealed. The newly accessible protein surface could have lectin-like activity and also be inherently antigenic. In addition, the more mobile G0 oligosaccharide can be recognised by mannose binding protein. As the mannose binding protein can activate complement, and the Fc oligosaccharide would not normally be accessible to protein recognition, this finding might suggest a specific role for the G0 glycoform in inflammation when the appropriate IgG glycoforms are clustered.