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Asymmetric Cryo-EM Structure of Anthrax Toxin Protective Antigen Pore with Lethal Factor N-Terminal Domain

1
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA
2
Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA
3
Departments of Biological Sciences and Bioengineering, Lehigh University, Bethlehem, PA 18015, USA
4
National Center for Macromolecular Imaging, Baylor University, Houston TX 77030, USA
5
Department of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110, USA
6
Electron Microscopy Core Facility, University of Missouri, Columbia, MO 65211, USA
*
Author to whom correspondence should be addressed.
These authors contributed to this work equally.
Academic Editor: Michel R. Popoff
Toxins 2017, 9(10), 298; https://doi.org/10.3390/toxins9100298
Received: 17 August 2017 / Revised: 18 September 2017 / Accepted: 19 September 2017 / Published: 22 September 2017
(This article belongs to the Special Issue Cellular Entry of Binary and Pore-Forming Bacterial Toxins)
The anthrax lethal toxin consists of protective antigen (PA) and lethal factor (LF). Understanding both the PA pore formation and LF translocation through the PA pore is crucial to mitigating and perhaps preventing anthrax disease. To better understand the interactions of the LF-PA engagement complex, the structure of the LFN-bound PA pore solubilized by a lipid nanodisc was examined using cryo-EM. CryoSPARC was used to rapidly sort particle populations of a heterogeneous sample preparation without imposing symmetry, resulting in a refined 17 Å PA pore structure with 3 LFN bound. At pH 7.5, the contributions from the three unstructured LFN lysine-rich tail regions do not occlude the Phe clamp opening. The open Phe clamp suggests that, in this translocation-compromised pH environment, the lysine-rich tails remain flexible and do not interact with the pore lumen region. View Full-Text
Keywords: anthrax toxin; lethal factor; protective antigen; pore formation; translocation; nanodisc; cryo-EM; cryoSPARC anthrax toxin; lethal factor; protective antigen; pore formation; translocation; nanodisc; cryo-EM; cryoSPARC
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Machen, A.J.; Akkaladevi, N.; Trecazzi, C.; O’Neil, P.T.; Mukherjee, S.; Qi, Y.; Dillard, R.; Im, W.; Gogol, E.P.; White, T.A.; Fisher, M.T. Asymmetric Cryo-EM Structure of Anthrax Toxin Protective Antigen Pore with Lethal Factor N-Terminal Domain. Toxins 2017, 9, 298.

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