A model of anthrax toxin lethal factor bound to protective antigen.

Lacy DB, Lin HC, Melnyk RA, Schueler-Furman O, Reither L, Cunningham K, Baker D, Collier RJ
Proc Natl Acad Sci U S A. 2005 102 (45): 16409-14

PMID: 16251269 · PMCID: PMC1283467 · DOI:10.1073/pnas.0508259102

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.

MeSH Terms (7)

Antigens, Bacterial Bacterial Toxins Dimerization Disulfides Models, Molecular Protein Structure, Secondary Static Electricity

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