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Antigen binding allosterically promotes Fc receptor recognition

A key question in immunology is whether antigen recognition and Fc receptor (FcR) binding are allosterically linked. This question is also relevant for therapeutic antibody design. Antibody Fab and Fc domains are connected by flexible unstructured hinge region. Fc chains have conserved glycosylation...

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Autores principales: Zhao, Jun, Nussinov, Ruth, Ma, Buyong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343797/
https://www.ncbi.nlm.nih.gov/pubmed/30212263
http://dx.doi.org/10.1080/19420862.2018.1522178
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author Zhao, Jun
Nussinov, Ruth
Ma, Buyong
author_facet Zhao, Jun
Nussinov, Ruth
Ma, Buyong
author_sort Zhao, Jun
collection PubMed
description A key question in immunology is whether antigen recognition and Fc receptor (FcR) binding are allosterically linked. This question is also relevant for therapeutic antibody design. Antibody Fab and Fc domains are connected by flexible unstructured hinge region. Fc chains have conserved glycosylation sites at Asn297, with each conjugated to a core heptasaccharide and forming biantennary Fc glycan. The glycans modulate the Fc conformations and functions. It is well known that the antibody Fab and Fc domains and glycan affect antibody activity, but whether these elements act independently or synergistically is still uncertain. We simulated four antibody complexes: free antibody, antigen-bound antibody, FcR-bound antibody, and an antigen-antibody-FcR complex. We found that, in the antibody’s “T/Y” conformation, the glycans, and the Fc domain all respond to antigen binding, with the antibody population shifting to two dominant clusters, both with the Fc-receptor binding site open. The simulations reveal that the Fc-glycan-receptor complexes also segregate into two conformational clusters, one corresponding to the antigen-free antibody-FcR baseline binding, and the other with an antigen-enhanced antibody-FcR interaction. Our study confirmed allosteric communications in antibody-antigen recognition and following FcR activation. Even though we observed allosteric communications through the IgG domains, the most important mechanism that we observed is the communication via population shift, stimulated by antigen binding and propagating to influence FcR recognition.
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spelling pubmed-63437972019-02-01 Antigen binding allosterically promotes Fc receptor recognition Zhao, Jun Nussinov, Ruth Ma, Buyong MAbs Report A key question in immunology is whether antigen recognition and Fc receptor (FcR) binding are allosterically linked. This question is also relevant for therapeutic antibody design. Antibody Fab and Fc domains are connected by flexible unstructured hinge region. Fc chains have conserved glycosylation sites at Asn297, with each conjugated to a core heptasaccharide and forming biantennary Fc glycan. The glycans modulate the Fc conformations and functions. It is well known that the antibody Fab and Fc domains and glycan affect antibody activity, but whether these elements act independently or synergistically is still uncertain. We simulated four antibody complexes: free antibody, antigen-bound antibody, FcR-bound antibody, and an antigen-antibody-FcR complex. We found that, in the antibody’s “T/Y” conformation, the glycans, and the Fc domain all respond to antigen binding, with the antibody population shifting to two dominant clusters, both with the Fc-receptor binding site open. The simulations reveal that the Fc-glycan-receptor complexes also segregate into two conformational clusters, one corresponding to the antigen-free antibody-FcR baseline binding, and the other with an antigen-enhanced antibody-FcR interaction. Our study confirmed allosteric communications in antibody-antigen recognition and following FcR activation. Even though we observed allosteric communications through the IgG domains, the most important mechanism that we observed is the communication via population shift, stimulated by antigen binding and propagating to influence FcR recognition. Taylor & Francis 2018-10-05 /pmc/articles/PMC6343797/ /pubmed/30212263 http://dx.doi.org/10.1080/19420862.2018.1522178 Text en © 2018 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Report
Zhao, Jun
Nussinov, Ruth
Ma, Buyong
Antigen binding allosterically promotes Fc receptor recognition
title Antigen binding allosterically promotes Fc receptor recognition
title_full Antigen binding allosterically promotes Fc receptor recognition
title_fullStr Antigen binding allosterically promotes Fc receptor recognition
title_full_unstemmed Antigen binding allosterically promotes Fc receptor recognition
title_short Antigen binding allosterically promotes Fc receptor recognition
title_sort antigen binding allosterically promotes fc receptor recognition
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343797/
https://www.ncbi.nlm.nih.gov/pubmed/30212263
http://dx.doi.org/10.1080/19420862.2018.1522178
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