TY - JOUR
T1 - A model of anthrax toxin lethal factor bound to protective antigen
AU - Lacy, D. Borden
AU - Lin, Henry C.
AU - Melnyk, Roman A.
AU - Schueler-Furman, Ora
AU - Reither, Laura
AU - Cunningham, Kristina
AU - Baker, David
AU - Collier, John R.
PY - 2005/11/8
Y1 - 2005/11/8
N2 - 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.
AB - 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.
KW - Computation
KW - Docking
KW - Electrostatic
UR - http://www.scopus.com/inward/record.url?scp=28044436994&partnerID=8YFLogxK
U2 - 10.1073/pnas.0508259102
DO - 10.1073/pnas.0508259102
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C2 - 16251269
AN - SCOPUS:28044436994
SN - 0027-8424
VL - 102
SP - 16409
EP - 16414
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 45
ER -
