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Title: Germline V-genes sculpt the binding site of a family of antibodies neutralizing human cytomegalovirus

Abstract

Immunoglobulin genes are generated somatically through specialized mechanisms resulting in a vast repertoire of antigen-binding sites. Despite the stochastic nature of these processes, the V-genes that encode most of the antigen-combining site are under positive evolutionary selection, raising the possibility that V-genes have been selected to encode key structural features of binding sites of protective antibodies against certain pathogens. Human, neutralizing antibodies to human cytomegalovirus that bind the AD-2S1 epitope on its gB envelope protein repeatedly use a pair of well-conserved, germline V-genes IGHV3-30 and IGKV3-11. Here, we present crystallographic, kinetic and thermodynamic analyses of the binding site of such an antibody and that of its primary immunoglobulin ancestor. These show that these germline V-genes encode key side chain contacts with the viral antigen and thereby dictate key structural features of the hypermutated, high-affinity neutralizing antibody. V-genes may thus encode an innate, protective immunological memory that targets vulnerable, invariant sites on multiple pathogens.

Authors:
; ; ; ; ;  [1]
  1. Toronto
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1006890
Resource Type:
Journal Article
Journal Name:
EMBO J.
Additional Journal Information:
Journal Volume: 27; Journal Issue: (19) ; 10, 2008; Journal ID: ISSN 0261-4189
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; ANTIBODIES; ANTIGEN-ANTIBODY REACTIONS; ANTIGENS; CRYSTALLOGRAPHY; GENES; HUMAN POPULATIONS; IMMUNOGLOBULINS; KINETICS; PATHOGENS; PROTEINS; TARGETS; THERMODYNAMICS; USES; VIRUSES

Citation Formats

Thomson, Christy A, Bryson, Steve, McLean, Gary R, Creagh, A Louise, Pai, Emil F, Schrader, John W, and UBC). Germline V-genes sculpt the binding site of a family of antibodies neutralizing human cytomegalovirus. United States: N. p., 2008. Web. doi:10.1038/emboj.2008.179.
Thomson, Christy A, Bryson, Steve, McLean, Gary R, Creagh, A Louise, Pai, Emil F, Schrader, John W, & UBC). Germline V-genes sculpt the binding site of a family of antibodies neutralizing human cytomegalovirus. United States. https://doi.org/10.1038/emboj.2008.179
Thomson, Christy A, Bryson, Steve, McLean, Gary R, Creagh, A Louise, Pai, Emil F, Schrader, John W, and UBC). 2008. "Germline V-genes sculpt the binding site of a family of antibodies neutralizing human cytomegalovirus". United States. https://doi.org/10.1038/emboj.2008.179.
@article{osti_1006890,
title = {Germline V-genes sculpt the binding site of a family of antibodies neutralizing human cytomegalovirus},
author = {Thomson, Christy A and Bryson, Steve and McLean, Gary R and Creagh, A Louise and Pai, Emil F and Schrader, John W and UBC)},
abstractNote = {Immunoglobulin genes are generated somatically through specialized mechanisms resulting in a vast repertoire of antigen-binding sites. Despite the stochastic nature of these processes, the V-genes that encode most of the antigen-combining site are under positive evolutionary selection, raising the possibility that V-genes have been selected to encode key structural features of binding sites of protective antibodies against certain pathogens. Human, neutralizing antibodies to human cytomegalovirus that bind the AD-2S1 epitope on its gB envelope protein repeatedly use a pair of well-conserved, germline V-genes IGHV3-30 and IGKV3-11. Here, we present crystallographic, kinetic and thermodynamic analyses of the binding site of such an antibody and that of its primary immunoglobulin ancestor. These show that these germline V-genes encode key side chain contacts with the viral antigen and thereby dictate key structural features of the hypermutated, high-affinity neutralizing antibody. V-genes may thus encode an innate, protective immunological memory that targets vulnerable, invariant sites on multiple pathogens.},
doi = {10.1038/emboj.2008.179},
url = {https://www.osti.gov/biblio/1006890}, journal = {EMBO J.},
issn = {0261-4189},
number = (19) ; 10, 2008,
volume = 27,
place = {United States},
year = {Fri Oct 17 00:00:00 EDT 2008},
month = {Fri Oct 17 00:00:00 EDT 2008}
}