Investigation of the interaction between the class I MHC-related Fc receptor and its immunoglobulin G ligand

The neonatal Fc receptor (FcRn) is structurally similar to class 1 major histocompatibility molecules. FcRn transports maternal immunoglobulin G (IgG) from ingested milk into the blood. IgG is bound at the pH of milk (pH 6.0–6.5) in the gut and released at the pH of blood (pH 7.5). We find that alteration of a histidine pair within the α3 domain of FcRn and of a nearby loop (the FcRn counterpart of the class I CD8-binding loop) affects the affinity for IgG. Inhibition studies suggest the involvement of the FcRn B_2-microglobulin domain in IgG binding. Fragment B of protein A inhibits FcRn binding to IgG, localizing the binding site on Fc for FcRn to the C_H2-C_H3 domain interface. Three histidines present at the C_H2-C_H3 domain interface of Fc could be partially responsible for the pH-dependent interaction between FcRn and IgG