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Diversification of ?-Augmentation Interactions between CDI Toxin/Immunity Proteins.


ABSTRACT: 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 ?-augmentation interaction, in which the toxin domain extends a ?-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 ?-hairpin interacts mainly through direct H-bond and ion-pair interactions, whereas the YPIII ?-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 ?-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 ?-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.

SUBMITTER: Morse RP 

PROVIDER: S-EPMC4658667 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Diversification of β-Augmentation Interactions between CDI Toxin/Immunity Proteins.

Morse Robert P RP   Willett Julia L E JL   Johnson Parker M PM   Zheng Jing J   Credali Alfredo A   Iniguez Angelina A   Nowick James S JS   Hayes Christopher S CS   Goulding Celia W CW  

Journal of molecular biology 20151009 23


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/C  ...[more]

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