THE CLASS-I MAJOR HISTOCOMPATIBILITY COMPLEX RELATED FC RECEPTOR SHOWS PH-DEPENDENT STABILITY DIFFERENCES CORRELATING WITH IMMUNOGLOBULIN BINDING AND RELEASE

Maternal immunoglobulin G (IgG) in milk is transported to the bloodstr eam of newborn rodents via an Fc receptor (FcRn) expressed in the gut. The receptor shows a striking structural similarity to class I major histocompatibility complex (MHC) molecules, being composed of a relate d heavy chain and the identical light chain (beta2-microglobulin). FcR n binds IgG at the pH of milk in the proximal intestine (pH 6.0-6.5) a nd releases it at the pH of blood (pH is similar to 7.5). We have comp ared the stability of a soluble form of FcRn in these two pH ranges an d find that the heterodimer is markedly more stable at the permissive pH for IgG binding. Using the rate of beta2m exchange as a correlate o f heterodimer stability, we find that exchange is more than 10 times s lower at pH 6. compared to pH 7.8. Thermal denaturation profiles of Fc Rn heterodimers at pH 8.0 indicate a two-step, sequential heavy-chain (T(m) = 52-degrees-C) and beta2m (T(m) = 67-degrees-C) denaturation. B y contrast, at pH 6.0, a single transition is observed, centered at 62 -degrees-C, corresponding to denaturation of both chains. The striking difference in stability does not appear to be correlated with the bin ding of peptide as in class I MHC molecules, because analysis of purif ied FcRn by acid dissociation and sequencing suggests that FcRn is not associated with cellular peptides. These results are indicative of pH -dependent conformational changes in the FcRn heterodimer, which may b e related to its physiological function.