The class I major histocompatibility complex related Fc receptor shows pH-dependent stability differences correlating with immunoglobulin binding and release
Abstract
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 (β2-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 -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 β2m 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 (T_m = 52 °C) and β2m (T_m = 67 °C) denaturation. By contrast, at pH 6.0, a single transition is observed, centeredat 62 °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.
Additional Information
© 1993 American Chemical Society. Published in print 1 August 1993. Supported by the Howard Hughes Medical Institute (L.N.G. and P.J.B.) and a postdoctoral fellowship from the Cancer Research Institute (M.R.). P.J.B. is a Pew Scholar and has a Young Investigator Award from the Cancer Research Institute. We thank Dr. Margaret Fahnestock for providing purified H-2Kd for the comparative acid elutions, Drs. Fahnestock and Ilana Tamir for performing experiments to assess the pH dependence of H-2Kd stability, the Caltech and USC Microchemical Facilities for sequence analyses, Dr. Lennart Logdberg for the anti-rat p2m monoclonal antibody, and R. M. Renny Feldman for modeling the FcRn structure based on the structure of HLA-A2. We also thank Dr. Michael Blum for earlier contributions to the FcRn project in our laboratory. We are grateful to Drs. Neil Simister, Margaret Fahnestock, Wilhelm Burmeister, and Roland Strong for critical reading of the manuscript.Additional details
- Eprint ID
- 75807
- Resolver ID
- CaltechAUTHORS:20170406-130428289
- Howard Hughes Medical Institute (HHMI)
- Cancer Research Institute
- Pew Charitable Trust
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2017-04-06Created from EPrint's datestamp field
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2021-11-15Created from EPrint's last_modified field