Conformational diversity facilitates antibody mutation trajectories and discrimination between foreign and self-antigens
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.
|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||Prof Daniel Christ|
|Publisher Name||PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/32855302|