Publications
Conformational diversity facilitates antibody mutation trajectories and discrimination between foreign and self-antigens
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.
Type | Journal |
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ISBN | 1091-6490 (Electronic) 0027-8424 (Linking) |
Authors | Burnett, D. L.; Schofield, P.; Langley, D. B.; Jackson, J.; Bourne, K.; Wilson, E.; Porebski, B. T.; Buckle, A. M.; Brink, R.; Goodnow, C. C.; Christ, D. |
Responsible Garvan Author | Professor Daniel Christ |
Publisher Name | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA |
Published Date | 2020-09-30 |
Published Volume | 117 |
Published Issue | 36 |
Published Pages | 22341-22350 |
Status | Published in-print |
DOI | 10.1073/pnas.2005102117 |
URL link to publisher's version | https://www.ncbi.nlm.nih.gov/pubmed/32855302 |