Article
- The EMBO Journal (2008) 27, 2592 - 2602
- doi:10.1038/emboj.2008.179
Published online: 4 September 2008
Subject Categories:
Germline V-genes sculpt the binding site of a family of antibodies neutralizing human cytomegalovirus
Christy A Thomson1, Steve Bryson2, Gary R McLean1,a, A Louise Creagh3, Emil F Pai4 and John W Schrader1
- The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada
- Department of Biochemistry, University of Toronto, and Division of Cancer Genomics & Proteomics, Ontario Cancer Institute, Toronto, Ontario, Canada
- Michael Smith Laboratories and the Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, British Columbia, Canada
- Departments of Biochemistry, Medical Biophysics and Molecular Genetics, University of Toronto, and Division of Cancer Genomics & Proteomics, Ontario Cancer Institute, Toronto, Ontario, Canada
Correspondence to:
John W Schrader, The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. Tel.: +1 604 822 7822; Fax: +1 604 822 7815; E-mail: john@brc.ubc.ca
aPresent address: Department of Respiratory Medicine, Imperial College, London, UK
Received 5 April 2008; Accepted 13 August 2008
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.
Keywords:
- germline antibody,
- human cytomegalovirus,
- immunological memory,
- structure,
- thermodynamics
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