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Diversification of β-Augmentation Interactions between CDI Toxin/Immunity Proteins.
Robert P Morse1, Julia L E Willett2, Parker M Johnson1
1Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697, USA.
Journal of Molecular Biology
|October 10, 2015
Summary
Contact-dependent growth inhibition (CDI) uses CdiA toxins and CdiI immunity proteins. Structural comparisons reveal distinct interactions, suggesting potential for small molecule inhibitors to disrupt bacterial competition.
Area of Science:
- Microbiology
- Structural Biology
- Evolutionary Biology
Background:
- Contact-dependent growth inhibition (CDI) is a key bacterial competition mechanism mediated by CdiB/CdiA secretion systems.
- CdiA toxins inhibit target cell growth, while CdiI immunity proteins provide self-protection.
- Understanding toxin-immunity interactions is crucial for deciphering bacterial competition dynamics.
Purpose of the Study:
- To compare the structures of CdiA-CT/CdiI complexes from E. coli and Y. pseudotuberculosis.
- To investigate the evolutionary divergence of CDI toxin-immunity protein interactions.
- To explore the potential for small molecule-based disruption of CDI.
Main Methods:
- Comparative structural analysis of homologous CdiA-CT/CdiI complexes using X-ray crystallography.
- Biochemical assays to confirm specificity of CdiI protection against cognate CdiA-CT.
- Synthesis and structural characterization of a peptide mimic inhibitor.
Main Results:
- Both E. coli and Y. pseudotuberculosis CdiA-CT/CdiI complexes utilize a conserved beta-augmentation interaction.
- Significant differences in interaction interfaces were observed, including hydrogen bonds, ion-pairs, hydrophobic contacts, and water molecules.
- Each CdiI protein demonstrated specific protection only against its cognate CdiA-CT toxin.
- A macrocyclic peptide mimic of the E. coli CdiA-CT beta-hairpin successfully bound its cognate CdiI.
Conclusions:
- The CDI toxin-immunity interface has evolved distinct interaction strategies in different bacterial species.
- The specificity of CdiI protection highlights the co-evolution of toxin and immunity components.
- The identified structural features and successful peptide mimic suggest a viable strategy for designing small molecule inhibitors to disrupt CDI.
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