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J Mol Model. 2016 Jan;22(1):7. doi: 10.1007/s00894-015-2878-8. Epub 2015 Dec 11.

Molecular assembly of lethal factor enzyme and pre-pore heptameric protective antigen in early stage of translocation.

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School of Pharmacy, H3423 Health Sciences Centre, Memorial University of Newfoundland, St. John's, NL, A1B 3V6, Canada.
Department of Chemistry, Faculty of Science, Memorial University of Newfoundland, St. John's, NL, Canada.
Department of Anatomy and Cell Biology, Groupe de recherche axé sur la structure des protéines (GRASP), Groupe d'Étude des Proteines Membranaires (GÉPROM), McGill University, 3640 University Street, Montreal, QC, H3A 2B2, Canada.


During intoxication, the anthrax toxin lethal (LF) and edema (EF) factors initially assemble with the protective antigen (PA) on the plasma membrane of cells expressing the membrane-bound surface-exposed anthrax toxin receptor (ATR). This takes place at the physiological pH prior to entering the acidic environment of the endosome. We elucidated the molecular dynamics (MD) behaviors of the three-dimensional structure of the (PA63)7LF3 complex in various conformations and analyzed the dynamical properties of the fully loaded pre-pore complex on the plasma membrane at the physiological pH. The analysis points to the interaction networks of amino acids conserved between PA63 octamer and heptamer, which are not affected during the initial stage of the LFs binding. The simulations show an asymmetrical movement of the complex domains that directly affect LFs conformations. The conformational and structural alterations of the 2β2-2β3 loops of PA subunits are associated with pore formation. The early conformational changes of the loops appear as they peel off from the domain 2 toward domain 4 of each PA subunit. The LFs unfold in 1α1 segments of their N-terminal initiating the early stage of the pre-pore formation. The results indicate instable regions within the complex and provide important clues concerning the detail of fluctuating residues of the LF-PA interface regions at the early steps of toxins translocation.


Anthrax toxin; Complexation stoichiometry; Domains motilities; LF unfolding; Lumen asynchronous alterations

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