INVESTIGATION OF THE INTERACTION BETWEEN THE CLASS-I MHC-RELATED FC RECEPTOR AND ITS IMMUNOGLOBULIN-G LIGAND

The neonatal Fe receptor (FcRn) is structurally similar to class I 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 alpha 3 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(H)2-C(H)3 domain interface. Three histidines present at the C(H)2-C(H)3 domain interface of Fc could be partially responsible for the pH-dependent interaction between FcRn and IgG.