High affinity IgG binding by FcgammaRI (CD64) is modulated by two distinct IgSF domains and the transmembrane domain of the receptor.
The high affinity IgG receptor, FcgammaRI, is comprised of three immunoglobulin superfamily (IgSF) domains (EC1, EC2 and EC3), a single transmembrane spanning region, and a short cytoplasmic tail. We have shown a role for three separate domains of FcgammaRI in the high affinity binding of IgG. Affinity measurements of chimeric FcgammaRs in which EC1 and EC2 of FcgammaRI have been replaced with the homologous EC1 and/or EC2 domains of the low affinity IgG receptor, FcgammaRII indicate that both EC2 and EC3 are essential for high affinity binding of monomeric IgG. Identification of EC3 from FcgammaRI as the binding site for the monoclonal antibody 10.1, which blocks IgG binding, provides further evidence for the role of this domain in binding. In addition, we have found that the affinity of FcgammaRI is increased threefold when co-expressed with its accessory molecule, gamma-chain. Affinity measurements of further chimeras indicates that the transmembrane domain of FcgammaRI has a negative influence upon the affinity of the receptor. To account for these observations, we propose that receptor dimerization is required for maximal affinity of FcgammaRI. Dimerization may serve as the mechanism by which IgG binding triggers several FcgammaRI-mediated events.
Harrison
P T
PT
Department of Medicine and Therapeutics, The University of Glasgow, UK.
Allen
J M
JM
D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000937:Antigen-Antibody Reactions; D001665:Binding Sites / Q000235:genetics / Q000276:immunology / Q000502:physiology; D019556:COS Cells; D018604:Epitope Mapping; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D007142:Immunoglobulin gamma-Chains / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D008024:Ligands; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D017452:Receptors, IgG / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D012107:Research Design; D013329:Structure-Activity Relationship
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D007142:Immunoglobulin gamma-Chains; D008024:Ligands; D008565:Membrane Proteins; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins