Conformational diversity facilitates antibody mutation trajectories and discrimination between foreign and self-antigens

Deborah L. Burnett, Peter Schofield, David B. Langley, Jennifer Jackson, Katherine Bourne, Emily Wilson, Benjamin T. Porebski, Ashley M. Buckle, Robert Brink, Christopher C. Goodnow, Daniel Christ

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

Conformational diversity and self-cross-reactivity of antigens have been correlated with evasion from neutralizing antibody responses. We utilized single cell B cell sequencing, biolayer interferometry and X-ray crystallography to trace mutation selection pathways where the antibody response must resolve cross-reactivity between foreign and self-proteins bearing near-identical contact surfaces, but differing in conformational flexibility. Recurring antibody mutation trajectories mediate long-range rearrangements of framework (FW) and complementarity determining regions (CDRs) that increase binding site conformational diversity. These antibody mutations decrease affinity for self-antigen 19-fold and increase foreign affinity 67-fold, to yield a more than 1,250-fold increase in binding discrimination. These results demonstrate how conformational diversity in antigen and antibody does not act as a barrier, as previously suggested, but rather facilitates high affinity and high discrimination between foreign and self.

Original languageEnglish
Pages (from-to)22341-22350
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number36
DOIs
Publication statusPublished - 8 Sep 2020

Keywords

  • Affinity maturation
  • Autoantibody redemption
  • Clonal selection
  • Humoral immunity
  • Somatic hypermutation

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