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Delineation of the Amino Acid Residues Involved in Transcytosis and Catabolism of Mouse IgG1

Delineation of the Amino Acid Residues Involved in Transcytosis and Catabolism of Mouse IgG1
Delineation of the Amino Acid Residues Involved in Transcytosis and Catabolism of Mouse IgG1

The MHC class I-related receptor, FcRn, is involved in both the transcytosis of serum γ-globulins (IgGs) and in regulating their serum persistence. The interaction site of FcRn on the Fc region of rodent IgG has been mapped to residues at the CH2-CH3 domain interface using site-directed mutagenesis and x-ray crystallographic analyses. In the current study, the role of individual residues (H310, H433, and N434) at this interface in mediating the Fc-FcRn interaction has been investigated using recombinant, mutated Fc hinge fragments derived from mouse IgG1. In addition, two highly conserved Fc histidines (H435 and H436) have been mutated to alanine, and the resulting mutated Fc hinge fragments were analyzed in both transcytosis and pharmacokinetic studies in mice and in competition binding assays using recombinant, soluble FcRn. The analyses indicate that mutation of H310, H435, and, to a lesser extent, H436 to alanine results in reduced activity of the Fc hinge fragments in both in vivo and in vitro assays. Thus, in addition to the previously defined role of I253 in the FcRn-IgG interaction, these histidines play a key role in mediating the functions conducted by this Fc receptor. The effects of these mutations on binding of Fc hinge fragments to staphylococcal protein A have also been analyzed and demonstrate a partial, but not complete, overlap of the FcRn and staphylococcal protein A interaction sites on mouse IgG1.

0022-1767
2211-2217
Medesan, Corneliu
0de1d9e4-c8d9-4896-bcca-63f8b24e8f2c
Matesoi, Diana
0ed9f055-aaa2-4d84-a478-f45852460980
Radu, Caius
cf50ccf6-c03c-4d8f-abd8-56681251f990
Ghetie, Victor
b7b50946-2bd9-4896-b841-6bbfba8237c2
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc
Medesan, Corneliu
0de1d9e4-c8d9-4896-bcca-63f8b24e8f2c
Matesoi, Diana
0ed9f055-aaa2-4d84-a478-f45852460980
Radu, Caius
cf50ccf6-c03c-4d8f-abd8-56681251f990
Ghetie, Victor
b7b50946-2bd9-4896-b841-6bbfba8237c2
Ward, E. Sally
b31c0877-8abe-485f-b800-244a9d3cd6cc

Medesan, Corneliu, Matesoi, Diana, Radu, Caius, Ghetie, Victor and Ward, E. Sally (1997) Delineation of the Amino Acid Residues Involved in Transcytosis and Catabolism of Mouse IgG1. The Journal of Immunology, 158 (5), 2211-2217.

Record type: Article

Abstract

The MHC class I-related receptor, FcRn, is involved in both the transcytosis of serum γ-globulins (IgGs) and in regulating their serum persistence. The interaction site of FcRn on the Fc region of rodent IgG has been mapped to residues at the CH2-CH3 domain interface using site-directed mutagenesis and x-ray crystallographic analyses. In the current study, the role of individual residues (H310, H433, and N434) at this interface in mediating the Fc-FcRn interaction has been investigated using recombinant, mutated Fc hinge fragments derived from mouse IgG1. In addition, two highly conserved Fc histidines (H435 and H436) have been mutated to alanine, and the resulting mutated Fc hinge fragments were analyzed in both transcytosis and pharmacokinetic studies in mice and in competition binding assays using recombinant, soluble FcRn. The analyses indicate that mutation of H310, H435, and, to a lesser extent, H436 to alanine results in reduced activity of the Fc hinge fragments in both in vivo and in vitro assays. Thus, in addition to the previously defined role of I253 in the FcRn-IgG interaction, these histidines play a key role in mediating the functions conducted by this Fc receptor. The effects of these mutations on binding of Fc hinge fragments to staphylococcal protein A have also been analyzed and demonstrate a partial, but not complete, overlap of the FcRn and staphylococcal protein A interaction sites on mouse IgG1.

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More information

Published date: 1 March 1997

Identifiers

Local EPrints ID: 425117
URI: https://eprints.soton.ac.uk/id/eprint/425117
ISSN: 0022-1767
PURE UUID: f7aed647-2be4-4d9b-9954-480da7cc3d44
ORCID for E. Sally Ward: ORCID iD orcid.org/0000-0003-3232-7238

Catalogue record

Date deposited: 11 Oct 2018 16:30
Last modified: 14 Mar 2019 01:21

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Contributors

Author: Corneliu Medesan
Author: Diana Matesoi
Author: Caius Radu
Author: Victor Ghetie
Author: E. Sally Ward ORCID iD

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