Analysis of Fc gamma RIII and IgG Fc polymorphism reveals functional and evolutionary implications of protein-protein interaction

Fc gamma receptor III (Fc gamma RIII), a low-affinity receptor for the Fc p ortion of immunoglobulin G (Ige Fc), targets antigen-antibody complexes in a variety of effector cells of the immune system. We have investigated Fc g amma RIII and Ige Fc polymorphism and made comparative analysis of the func tional and evolutionary implications of the interaction between these two m olecules. Sequence analysis and comparison of the three-dimensional structu re suggest that the C-terminal Ig domain of Fc gamma RIII is associated wit h the binding of IgC. The polymorphic residues of Fc gamma RIII are mainly located in the region of the C-terminal Ig domain that might be involved in Ige binding. Therefore, polymorphism and Functional binding affinity seems to be related to each other as has been increasingly implicated in clinica l observations. IgG Fcs, the natural ligand of Fc gamma Rs, also exhibit si gnificant polymorphism. Three regions have been identified where polymorphi sm frequently occurs: the putative FcR binding site, the linker region, and the intermolecular domain-domain interface of the second Ig domain. The pu tative Fc gammaR binding sites where polymorphic, and isotype-specific resi dues cluster are consistent with the regions that have been identified by m utagenesis and molecular modeling studies. The polymorphic residues of IgG Fc were mainly located in the molecular surface, which could be used in the recognition of other binding molecules. These observations suggest that po lymorphic and isotype-specific residues in IgG Fc are closely related to th eir function and protein-protein interaction. Therefore, the colocalization of the polymorphic residues of Fc gamma RIII and Ige Fcs at their docking sites implies that the polymorphic residues would affect the IgG-Fc gamma R III binding interactions to optimize their signaling through evolution.