Diversification of β-augmentation interactions between CDI toxin/immunity proteins

Robert P. Morse, Julia L.E. Willett, Parker M. Johnson, Jing Zheng, Alfredo Credali, Angelina Iniguez, James S. Nowick, Christopher S. Hayes, Celia W. Goulding

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Contact-dependent growth inhibition (CDI) is a widespread mechanism of inter-bacterial competition mediated by the CdiB/CdiA family of two-partner secretion proteins. CdiA effectors carry diverse C-terminal toxin domains (CdiA-CT), which are delivered into neighboring target cells to inhibit growth. CDI+ bacteria also produce CdiI immunity proteins that bind specifically to cognate CdiA-CT toxins and protect the cell from auto-inhibition. Here, we compare the structures of homologous CdiA-CT/CdiI complexes from Escherichia coli EC869 and Yersinia pseudotuberculosis YPIII to explore the evolution of CDI toxin/immunity protein interactions. Both complexes share an unusual β-augmentation interaction, in which the toxin domain extends a β-hairpin into the immunity protein to complete a six-stranded anti-parallel sheet. However, the specific contacts differ substantially between the two complexes. The EC869 β-hairpin interacts mainly through direct H-bond and ion-pair interactions, whereas the YPIII β-hairpin pocket contains more hydrophobic contacts and a network of bridging water molecules. In accord with these differences, we find that each CdiI protein only protects target bacteria from its cognate CdiA-CT toxin. The compact β-hairpin binding pocket within the immunity protein represents a tractable system for the rationale design of small molecules to block CdiA-CT/CdiI complex formation. We synthesized a macrocyclic peptide mimic of the β-hairpin from EC869 toxin and solved its structure in complex with cognate immunity protein. These latter studies suggest that small molecules could potentially be used to disrupt CDI toxin/immunity complexes.

Original languageEnglish (US)
Pages (from-to)3766-3784
Number of pages19
JournalJournal of Molecular Biology
Issue number23
StatePublished - Nov 20 2015


  • DNase
  • bacterial competition
  • interspecies growth inhibition
  • toxin/immunity proteins

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    Morse, R. P., Willett, J. L. E., Johnson, P. M., Zheng, J., Credali, A., Iniguez, A., Nowick, J. S., Hayes, C. S., & Goulding, C. W. (2015). Diversification of β-augmentation interactions between CDI toxin/immunity proteins. Journal of Molecular Biology, 427(23), 3766-3784. https://doi.org/10.1016/j.jmb.2015.09.020