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MAbs. 2018 Oct 5:1-17. doi: 10.1080/19420862.2018.1522178. [Epub ahead of print]

Antigen binding allosterically promotes Fc receptor recognition.

Author information

1
a Cancer and Inflammation Program , National Cancer Institute , Frederick , Maryland , USA.
2
b Basic Science Program , Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute , Frederick , Maryland , USA.
3
c Sackler Inst. of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine , Tel Aviv University , Tel Aviv , Israel.

Abstract

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.

KEYWORDS:

allosteric effects; allostery; antibody; conformational selection

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