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    Structure of the anthrax protective antigen D425A dominant negative mutant reveals a stalled intermediate state of pore maturation

    Date
    2022-05-15
    Author
    Scott, Harry
    Huang, Wei
    Andra, Kiran K.
    Mamillapalli, Sireesha
    Gonti, Srinivas
    Day, Alexander
    Zhang, Kaiming
    Mehzabeen, Nurjahan
    Battaile, Kevin P.
    Raju, Anjali
    Lovell, Scott
    Bann, James G.
    Taylor, Derek J.
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    Citation
    Scott, H., Huang, W., Andra, K., Mamillapalli, S., Gonti, S., Day, A., . . . Taylor, D. J. (2022). Structure of the Anthrax Protective Antigen D425A Dominant Negative Mutant Reveals a Stalled Intermediate State of Pore Maturation. Journal of Molecular Biology, 434(9). https://doi.org/https://doi.org/10.1016/j.jmb.2022.167548
    Abstract
    The tripartite protein complex produced by anthrax bacteria (Bacillus anthracis) is a member of the AB family of β-barrel pore-forming toxins. The protective antigen (PA) component forms an oligomeric prepore that assembles on the host cell surface and serves as a scaffold for binding of lethal and edema factors. Following endocytosis, the acidic environment of the late endosome triggers a pH-induced conformational rearrangement to promote maturation of the PA prepore to a functional, membrane spanning pore that facilitates delivery of lethal and edema factors to the cytosol of the infected host. Here, we show that the dominant-negative D425A mutant of PA stalls anthrax pore maturation in an intermediate state at acidic pH. Our 2.7 Å cryo-EM structure of the intermediate state reveals structural rearrangements that involve constriction of the oligomeric pore combined with an intramolecular dissociation of the pore-forming module. In addition to defining the early stages of anthrax pore maturation, the structure identifies asymmetric conformational changes in the oligomeric pore that are influenced by the precise configuration of adjacent protomers.
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    URI
    https://doi.org/10.1016/j.jmb.2022.167548
    https://soar.wichita.edu/handle/10057/23381
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