Proteolytic processing induces a conformational switch required for antibacterial toxin delivery

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. Basra, Ricardo Cortes, Zainab Noorsher, Youssef Gabraiel, Isaac Poonen-Honig, Elizabeth C. Seacord, Celia W. Goulding, David A. Low, Andrzej Joachimiak, Frederick W. Dahlquist and Christopher S. Hayes ()
Additional contact information
Nicholas L. Bartelli: University of California
Victor J. Passanisi: University of California
Karolina Michalska: 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
David A. Low: University of California
Andrzej Joachimiak: Argonne National Laboratory
Frederick W. Dahlquist: University of California
Christopher S. Hayes: University of California

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32795-y

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