HIGH-AFFINITY IGG BINDING BY FC-GAMMA-RI (CD64) IS MODULATED BY 2 DISTINCT IGSF DOMAINS AND THE TRANSMEMBRANE DOMAIN OF THE RECEPTOR

The high affinity IgG receptor, Fc gamma RI, is comprised of three imm unoglobulin superfamily (IgSF) domains (EC1, EC2 and EC3), a single tr ansmembrane spanning region, and a short cytoplasmic tail. We have sho wn a role for three separate domains of Fc gamma RI in the high affini ty binding of IgG, Affinity measurements of chimeric Fc gamma Rs in wh ich EC1 and EC2 of Fc gamma RI have been replaced with the homologous EC1 and/or EC2 domains of the low affinity IgG receptor, Fc gamma RII indicate that both EC2 and EC3 are essential for high affinity binding of monomeric IgG, Identification of EC3 from Fc gamma RI as the bindi ng site for the monoclonal antibody 10.1, which blocks IgG binding, pr ovides further evidence for the role of this domain in binding. In add ition, we have found that the affinity of Fc gamma RI is increased thr eefold when co-expressed with its accessory molecule, gamma-chain. Aff inity measurements of further chimeras indicates that the transmembran e domain of Fc gamma RI has a negative influence upon the affinity of the receptor. To account for these observations, we propose that recep tor dimerization is required for maximal affinity of Fc gamma RI, Dime rization may serve as the mechanism by which IgG binding triggers seve ral Fc gamma RI-mediated events.