The neonatal Fc receptor (FcRn) transports maternal IgG in ingested milk to the bloodstream of the newborn. IgG binds to FcRn on the apical side of intestinal epithelial cells at pH 6; FcRn/IgG complexes are transcytosed to the basolateral side of the cell where IgG is released at pH 7.4. The three-dimensional structures of FcRn and FcRn/Fc are known and suggest that FcRn dimerizes in response to IgG binding. The investigator hypothesizes that formation of an """"""""oligomeric ribbon"""""""" of FcRn dimers on adjacent membranes bridged by IgG molecules is also required for FcRn function. This proposal aims at (i) understanding the roles of the FcRn dimer and oligomeric ribbon of FcRn dimers in IgG binding and transcytosis, (ii) dissecting the molecular basis for the pH dependence of the FcRn/IgG interaction, and (iii) understanding the significance of the closure of the FcRn counterpart of the MHC peptide-binding groove. To answer the first question, the binding affinities of site-directed mutants of FcRn which do not dimerize, and of Fc mutants that contact only one of the FcRn molecules in the FcRn dimer, will be measured by BIAcore. A hybrid Fc, in which a wild type Fc chain is paired with a mutant Fc chain that does not bind FcRn, will be used to determine if bridging of FcRn molecules by IgG is required for transcytosis. To answer the second question, Hill plot analysis of the pH-dependent affinity transitions of mutant complexes will be carried out to identify which residues mediate the transition. The crystal structure of FcRn at pH 8.0 will be determined and compared with that at pH 6.5 to address the possibility of pH-dependent conformational changes. To answer the third question, mutants of FcRn with an open, MHC-like peptide-binding groove will be constructed and characterized.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041239-02
Application #
2672982
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1997-04-01
Project End
2002-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Donaldson, G P; Ladinsky, M S; Yu, K B et al. (2018) Gut microbiota utilize immunoglobulin A for mucosal colonization. Science 360:795-800
Stadtmueller, Beth M; Yang, Zhongyu; Huey-Tubman, Kathryn E et al. (2016) Biophysical and Biochemical Characterization of Avian Secretory Component Provides Structural Insights into the Evolution of the Polymeric Ig Receptor. J Immunol 197:1408-14
Ahmed, Alysia A; Keremane, Sravya R; Vielmetter, Jost et al. (2016) Structural characterization of GASDALIE Fc bound to the activating Fc receptor Fc?RIIIa. J Struct Biol 194:78-89
Stadtmueller, Beth M; Huey-Tubman, Kathryn E; López, Carlos J et al. (2016) The structure and dynamics of secretory component and its interactions with polymeric immunoglobulins. Elife 5:
Ndjamen, Blaise; Joshi, Devashish S; Fraser, Scott E et al. (2016) Characterization of Antibody Bipolar Bridging Mediated by the Human Cytomegalovirus Fc Receptor gp68. J Virol 90:3262-7
Ahmed, Alysia A; Giddens, John; Pincetic, Andrew et al. (2014) Structural characterization of anti-inflammatory immunoglobulin G Fc proteins. J Mol Biol 426:3166-3179
Ndjamen, Blaise; Farley, Alexander H; Lee, Terri et al. (2014) The herpes virus Fc receptor gE-gI mediates antibody bipolar bridging to clear viral antigens from the cell surface. PLoS Pathog 10:e1003961
Hamburger, Zsuzsa A; Hamburger, Agnes E; West Jr, Anthony P et al. (2006) Crystal structure of the S.cerevisiae exocyst component Exo70p. J Mol Biol 356:9-21
West Jr, Anthony P; Herr, Andrew B; Bjorkman, Pamela J (2004) The chicken yolk sac IgY receptor, a functional equivalent of the mammalian MHC-related Fc receptor, is a phospholipase A2 receptor homolog. Immunity 20:601-10
Martin, W L; West Jr, A P; Gan, L et al. (2001) Crystal structure at 2.8 A of an FcRn/heterodimeric Fc complex: mechanism of pH-dependent binding. Mol Cell 7:867-77

Showing the most recent 10 out of 18 publications