STRUCTURAL ANALYSIS OF A PROTEIN COMPLEX IN THE IMMUNE SYSTEM. P.J. Bjorkman, W.P. Burmeister, M. Raghavan, D.E. Vaughn, California, Institute of Technology, Pasadena, CA 91125

Maternal immunoglobulin G (IgG) in milk is transported to the bloodstream of newborn rodents via an Fc receptor (FcRn) expressed in the gut. FcRn binds IgG at the pH of milk in the intestine (pH 6.0 - 6.5) and releases IgG at the pH of blood (pH 7.5). The receptor shows a striking similarity to class I MHC molecules. Because the structures of MHC molecules appear uniquely adapted to their peptide binding function, it is surprising to find a molecule with a structural similarity, yet a completely different function in the immune system. The 2.2 A crystal structure of soluble FcRn is similar to structures of class I MHC molecules. Although the two helices that form the sides of the MHC peptide binding groove on the tops of the alpha1 and alpha2 domains are present in FcRn, they are closer together than their MHC counterparts, rendering the FcRn groove incapable of binding peptides. Together with biochemical and structural data from an FcRn/Fc complex, the FcRn structure suggests a unique utilization of the MHC fold for immune recognition, differing substantially from modes of MHC interactions with peptides, T cell receptors or CD8. The co-crystal structure shows that FcRn binds to Fc at the interface between the Fc CH2 and CH3 domains, which contains several histidine residues that could account for the sharply pH dependent FcRn/IgG interaction . A dimer of FcRn heterodimers observed in the co-crystals and in the crystals of FcRn alone could be involved in binding Fc, correlating with the 2:1 binding stoichiometry between FcRn and IgG, and suggests an unusual orientation of FcRn on the membrane.