Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes
Abstract
RTX leukotoxins are a diverse family of prokaryotic virulence factors that are secreted by the type 1 secretion system (T1SS) and target leukocytes to subvert host defenses. T1SS substrates all contain a C-terminal RTX domain that mediates recruitment to the T1SS and drives secretion via a Brownian ratchet mechanism. Neutralizing antibodies against the Bordetella pertussis adenylate cyclase toxin, an RTX leukotoxin essential for B . pertussis colonization, have been shown to target the RTX domain and prevent binding to the α M β 2 integrin receptor. Knowledge of the mechanisms by which antibodies bind and neutralize RTX leukotoxins is required to inform structure-based design of bacterial vaccines, however, no structural data are available for antibody binding to any T1SS substrate. Here, we determine the crystal structure of an engineered RTX domain fragment containing the α M β 2 -binding site bound to two neutralizing antibodies. Notably, the receptor-blocking antibodies bind to the linker regions of RTX blocks I–III, suggesting they are key neutralization-sensitive sites within the RTX domain and are likely involved in binding the α M β 2 receptor. As the engineered RTX fragment contained these key epitopes, we assessed its immunogenicity in mice and showed that it elicitsmore »
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER)
- OSTI Identifier:
- 1823293
- Alternate Identifier(s):
- OSTI ID: 1821247; OSTI ID: 1829858
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Published Article
- Journal Name:
- PLoS Pathogens
- Additional Journal Information:
- Journal Name: PLoS Pathogens Journal Volume: 17 Journal Issue: 9; Journal ID: ISSN 1553-7374
- Publisher:
- Public Library of Science (PLoS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Goldsmith, Jory A., DiVenere, Andrea M., Maynard, Jennifer A., McLellan, Jason S., and Sondermann, ed., Holger. Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes. United States: N. p., 2021.
Web. doi:10.1371/journal.ppat.1009920.
Goldsmith, Jory A., DiVenere, Andrea M., Maynard, Jennifer A., McLellan, Jason S., & Sondermann, ed., Holger. Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes. United States. https://doi.org/10.1371/journal.ppat.1009920
Goldsmith, Jory A., DiVenere, Andrea M., Maynard, Jennifer A., McLellan, Jason S., and Sondermann, ed., Holger. Tue .
"Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes". United States. https://doi.org/10.1371/journal.ppat.1009920.
@article{osti_1823293,
title = {Structural basis for antibody binding to adenylate cyclase toxin reveals RTX linkers as neutralization-sensitive epitopes},
author = {Goldsmith, Jory A. and DiVenere, Andrea M. and Maynard, Jennifer A. and McLellan, Jason S. and Sondermann, ed., Holger},
abstractNote = {RTX leukotoxins are a diverse family of prokaryotic virulence factors that are secreted by the type 1 secretion system (T1SS) and target leukocytes to subvert host defenses. T1SS substrates all contain a C-terminal RTX domain that mediates recruitment to the T1SS and drives secretion via a Brownian ratchet mechanism. Neutralizing antibodies against the Bordetella pertussis adenylate cyclase toxin, an RTX leukotoxin essential for B . pertussis colonization, have been shown to target the RTX domain and prevent binding to the α M β 2 integrin receptor. Knowledge of the mechanisms by which antibodies bind and neutralize RTX leukotoxins is required to inform structure-based design of bacterial vaccines, however, no structural data are available for antibody binding to any T1SS substrate. Here, we determine the crystal structure of an engineered RTX domain fragment containing the α M β 2 -binding site bound to two neutralizing antibodies. Notably, the receptor-blocking antibodies bind to the linker regions of RTX blocks I–III, suggesting they are key neutralization-sensitive sites within the RTX domain and are likely involved in binding the α M β 2 receptor. As the engineered RTX fragment contained these key epitopes, we assessed its immunogenicity in mice and showed that it elicits similar neutralizing antibody titers to the full RTX domain. The results from these studies will support the development of bacterial vaccines targeting RTX leukotoxins, as well as next-generation B . pertussis vaccines.},
doi = {10.1371/journal.ppat.1009920},
journal = {PLoS Pathogens},
number = 9,
volume = 17,
place = {United States},
year = {Tue Sep 21 00:00:00 EDT 2021},
month = {Tue Sep 21 00:00:00 EDT 2021}
}
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