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 bloodstream 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 related heavy chain and the identical light chain (beta 2-microglobulin). FcRn binds IgG at the pH of milk in the proximal intestine (pH 6.0-6.5) and releases it at the pH of blood (pH approximately 7.5). We have compared the stability of a soluble form of FcRn in these two pH ranges and find that the heterodimer is markedly more stable at the permissive pH for IgG binding. Using the rate of beta 2m exchange as a correlate of heterodimer stability, we find that exchange is more than 10 times slower at pH 6.1 compared to pH 7.8. Thermal denaturation profiles of FcRn heterodimers at pH 8.0 indicate a two-step, sequential heavy-chain (Tm = 52 degrees C) and beta 2m (Tm = 67 degrees C) denaturation. By 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 binding of peptide as in class I MHC molecules, because analysis of purified 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 be related to its physiological function.
Raghavan
M
M
Division of Biology, California Institute of Technology, Pasadena 91125.
Gastinel
L N
LN
Bjorkman
P J
PJ
D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D006183:H-2 Antigens / Q000276:immunology*; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000378:metabolism*; D007700:Kinetics; D008745:Methylation; D008892:Milk / Q000276:immunology; D011489:Protein Denaturation; D051381:Rats; D011961:Receptors, Fc / Q000302:isolation & purification / Q000378:metabolism*; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000378:metabolism; D013816:Thermodynamics; D001613:beta 2-Microglobulin / Q000302:isolation & purification / Q000378:metabolism
D006183:H-2 Antigens; C024755:H-2K(K) antigen; D007074:Immunoglobulin G; D011961:Receptors, Fc; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin