IgG-Fc-mediated effector functions: molecular definition of interaction sites for effector ligands and the role of glycosylation.
The Fc region of human IgG expresses interaction sites for many effector ligands. In this review the topographical distributions of ten of these sites are discussed in relation to functional requirement. It is apparent that interaction sites localised to the inter-CH2-CH3 domain region of the Fc allow for functional divalency, whereas sites localised to the hinge proximal region of the CH2 domain are functionally monovalent, with expression of the latter sites being particularly dependent on glycosylation. All x-ray crystal structures for Fc and Fc-ligand complexes report that the protein structure of the hinge proximal region of the CH2 domain is "disordered", suggesting "internal mobility". We propose a model in which such "internal mobility" results in the generation of a dynamic equilibrium between multiple conformers, certain of which express interaction sites specific to individual ligands. The emerging understanding of the influence of oligosaccharide/protein interactions on protein conformation and biological function of IgG antibodies suggests a potential to generate novel glycoforms of antibody molecules having unique profiles of effector functions.
Department of Immunology, Medical School, University of Birmingham, Edgbaston, UK. R.Jefferis@bham.ac.uk
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Pound
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D001665:Binding Sites; D002236:Carbohydrate Conformation; D002352:Carrier Proteins / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D007074:Immunoglobulin G / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D037241:Mannose-Binding Lectins; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017452:Receptors, IgG / Q000378:metabolism; D012217:Rheumatoid Factor / Q000378:metabolism
D001426:Bacterial Proteins; D002352:Carrier Proteins; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D008024:Ligands; D037241:Mannose-Binding Lectins; D009844:Oligosaccharides; D017452:Receptors, IgG; D012217:Rheumatoid Factor