A model of anthrax toxin lethal factor bound to protective antigen

TitleA model of anthrax toxin lethal factor bound to protective antigen
Publication TypeJournal Article
Year of Publication2005
AuthorsLacy, B. D., Lin H. C., Melnyk R. A., Schueler-Furman O., Reither L., Cunningham K., Baker D., & Collier J. R.
JournalProceedings of the National Academy of Sciences of the United States of America
Date Published2005 Nov 8
KeywordsAntigens, Bacterial, Bacterial Toxins, Collaborative Publication, Dimerization, Disulfides, Models, Molecular, Protein Structure, Secondary, Static Electricity

Anthrax toxin is made up of three proteins: the edema factor (EF), lethal factor (LF) enzymes, and the multifunctional protective antigen (PA). Proteolytically activated PA heptamerizes, binds the EF/LF enzymes, and forms a pore that allows for EF/LF passage into host cells. Using directed mutagenesis, we identified three LF-PA contact points defined by a specific disulfide crosslink and two pairs of complementary charge-reversal mutations. These contact points were consistent with the lowest energy LF-PA complex found by using Rosetta protein-protein docking. These results illustrate how biochemical and computational methods can be combined to produce reliable models of large complexes. The model shows that EF and LF bind through a highly electrostatic interface, with their flexible N-terminal region positioned at the entrance of the heptameric PA pore and thus poised to initiate translocation in an N- to C-terminal direction.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
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