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Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage

Publication ,  Journal Article
Xu, H; Schmidt, AG; O'Donnell, T; Therkelsen, MD; Kepler, TB; Moody, MA; Haynes, BF; Liao, HX; Harrison, SC; Shaw, DE
Published in: Proteins: Structure, Function and Bioinformatics
April 1, 2015

Affinity maturation, the process in which somatic hypermutation and positive selection generate antibodies with increasing affinity for an antigen, is pivotal in acquired humoral immunity. We have studied the mechanism of affinity gain in a human B-cell lineage in which two main maturation pathways, diverging from a common ancestor, lead to three mature antibodies that neutralize a broad range of H1 influenza viruses. Previous work showed that increased affinity in the mature antibodies derives primarily from stabilization of the CDR H3 loop in the antigen-binding conformation. We have now used molecular dynamics simulations and existing crystal structures to identify potentially key maturation mutations, and we have characterized their effects on the CDR H3 loop and on antigen binding using further simulations and experimental affinity measurements, respectively. In the two maturation pathways, different contacts between light and heavy chains stabilize the CDR H3 loop. As few as two single-site mutations in each pathway can confer substantial loop stability, but none of them confers experimentally detectable stability on its own. Our results support models of the germinal center reaction in which two or more mutations can occur without concomitant selection and show how divergent pathways have yielded functionally equivalent antibodies.

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Published In

Proteins: Structure, Function and Bioinformatics

DOI

EISSN

1097-0134

ISSN

0887-3585

Publication Date

April 1, 2015

Volume

83

Issue

4

Start / End Page

771 / 780

Related Subject Headings

  • Bioinformatics
  • 08 Information and Computing Sciences
  • 06 Biological Sciences
  • 01 Mathematical Sciences
 

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Xu, H., Schmidt, A. G., O’Donnell, T., Therkelsen, M. D., Kepler, T. B., Moody, M. A., … Shaw, D. E. (2015). Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage. Proteins: Structure, Function and Bioinformatics, 83(4), 771–780. https://doi.org/10.1002/prot.24745
Xu, H., A. G. Schmidt, T. O’Donnell, M. D. Therkelsen, T. B. Kepler, M. A. Moody, B. F. Haynes, H. X. Liao, S. C. Harrison, and D. E. Shaw. “Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage.” Proteins: Structure, Function and Bioinformatics 83, no. 4 (April 1, 2015): 771–80. https://doi.org/10.1002/prot.24745.
Xu H, Schmidt AG, O’Donnell T, Therkelsen MD, Kepler TB, Moody MA, et al. Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage. Proteins: Structure, Function and Bioinformatics. 2015 Apr 1;83(4):771–80.
Xu, H., et al. “Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage.” Proteins: Structure, Function and Bioinformatics, vol. 83, no. 4, Apr. 2015, pp. 771–80. Scopus, doi:10.1002/prot.24745.
Xu H, Schmidt AG, O’Donnell T, Therkelsen MD, Kepler TB, Moody MA, Haynes BF, Liao HX, Harrison SC, Shaw DE. Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage. Proteins: Structure, Function and Bioinformatics. 2015 Apr 1;83(4):771–780.
Journal cover image

Published In

Proteins: Structure, Function and Bioinformatics

DOI

EISSN

1097-0134

ISSN

0887-3585

Publication Date

April 1, 2015

Volume

83

Issue

4

Start / End Page

771 / 780

Related Subject Headings

  • Bioinformatics
  • 08 Information and Computing Sciences
  • 06 Biological Sciences
  • 01 Mathematical Sciences