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Proteolytic processing induces a conformational switch required for antibacterial toxin delivery

Author

Listed:
  • Nicholas L. Bartelli

    (University of California)

  • Victor J. Passanisi

    (University of California)

  • Karolina Michalska

    (Argonne National Laboratory
    University of Chicago
    Argonne National Laboratory)

  • Kiho Song

    (University of California)

  • Dinh Q. Nhan

    (University of California)

  • Hongjun Zhou

    (University of California)

  • Bonnie J. Cuthbert

    (University of California)

  • Lucy M. Stols

    (Argonne National Laboratory)

  • William H. Eschenfeldt

    (Argonne National Laboratory)

  • Nicholas G. Wilson

    (University of California)

  • Jesse S. Basra

    (University of California)

  • Ricardo Cortes

    (University of California)

  • Zainab Noorsher

    (University of California)

  • Youssef Gabraiel

    (University of California)

  • Isaac Poonen-Honig

    (University of California)

  • Elizabeth C. Seacord

    (University of California)

  • Celia W. Goulding

    (University of California
    University of California)

  • David A. Low

    (University of California
    University of California)

  • Andrzej Joachimiak

    (Argonne National Laboratory
    University of Chicago
    Argonne National Laboratory
    University of Chicago)

  • Frederick W. Dahlquist

    (University of California
    University of California
    University of California)

  • Christopher S. Hayes

    (University of California
    University of California)

Abstract

Many Gram-negative bacteria use CdiA effector proteins to inhibit the growth of neighboring competitors. CdiA transfers its toxic CdiA-CT region into the periplasm of target cells, where it is released through proteolytic cleavage. The N-terminal cytoplasm-entry domain of the CdiA-CT then mediates translocation across the inner membrane to deliver the C-terminal toxin domain into the cytosol. Here, we show that proteolysis not only liberates the CdiA-CT for delivery, but is also required to activate the entry domain for membrane translocation. Translocation function depends on precise cleavage after a conserved VENN peptide sequence, and the processed ∆VENN entry domain exhibits distinct biophysical and thermodynamic properties. By contrast, imprecisely processed CdiA-CT fragments do not undergo this transition and fail to translocate to the cytoplasm. These findings suggest that CdiA-CT processing induces a critical structural switch that converts the entry domain into a membrane-translocation competent conformation.

Suggested Citation

  • Nicholas L. Bartelli & Victor J. Passanisi & Karolina Michalska & Kiho Song & Dinh Q. Nhan & Hongjun Zhou & Bonnie J. Cuthbert & Lucy M. Stols & William H. Eschenfeldt & Nicholas G. Wilson & Jesse S. , 2022. "Proteolytic processing induces a conformational switch required for antibacterial toxin delivery," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32795-y
    DOI: 10.1038/s41467-022-32795-y
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    References listed on IDEAS

    as
    1. Stephanie K. Aoki & Elie J. Diner & Claire t’Kint de Roodenbeke & Brandt R. Burgess & Stephen J. Poole & Bruce A. Braaten & Allison M. Jones & Julia S. Webb & Christopher S. Hayes & Peggy A. Cotter & , 2010. "A widespread family of polymorphic contact-dependent toxin delivery systems in bacteria," Nature, Nature, vol. 468(7322), pages 439-442, November.
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