Contact-Dependent Growth Inhibition (CDI) and CdiB/CdiA Two-Partner Secretion Proteins

Willett, Julia L. E.; Ruhe, Zachary C.; Goulding, Celia W.; Low, David A.; Hayes, Christopher S.

doi:10.1016/j.jmb.2015.09.010

Cited by 91 publications

(113 citation statements)

References 77 publications

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“…CdiB is an Omp85 transport protein that exports and presents toxic CdiA proteins on the cell surface. CdiA effectors range from 180 to 630 kDa depending on bacterial species (12), but each is predicted to form an elongated filament projecting from the inhibitor cell. Upon binding a specific receptor, CdiA transfers its C-terminal toxin domain (CdiA-CT) into the target bacterium through an incompletely understood translocation pathway (13, 14).…”

Section: Introductionmentioning

confidence: 99%

CdiA Effectors Use Modular Receptor-Binding Domains To Recognize Target Bacteria

Ruhe

Nguyen

Xiong

et al. 2017

mBio

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Contact-dependent growth inhibition (CDI) systems encode CdiA effectors, which bind to specific receptors on neighboring bacteria and deliver C-terminal toxin domains to suppress target cell growth. Two classes of CdiA effectors that bind distinct cell surface receptors have been identified, but the molecular basis of receptor specificity is not understood. Alignment of BamA-specific CdiAEC93 from Escherichia coli EC93 and OmpC-specific CdiAEC536 from E. coli 536 suggests that the receptor-binding domain resides within a central region that varies between the two effectors. In support of this hypothesis, we find that CdiAEC93 fragments containing residues Arg1358 to Phe1646 bind specifically to purified BamA. Moreover, chimeric CdiAEC93 that carries the corresponding sequence from CdiAEC536 is endowed with OmpC-binding activity, demonstrating that this region dictates receptor specificity. A survey of E. coli CdiA proteins reveals two additional effector classes, which presumably recognize distinct receptors. Using a genetic approach, we identify the outer membrane nucleoside transporter Tsx as the receptor for a third class of CdiA effectors. Thus, CDI systems exploit multiple outer membrane proteins to identify and engage target cells. These results underscore the modularity of CdiA proteins and suggest that novel effectors can be constructed through genetic recombination to interchange different receptor-binding domains and toxic payloads.

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Section: Introductionmentioning

confidence: 99%

CdiA Effectors Use Modular Receptor-Binding Domains To Recognize Target Bacteria

Ruhe

Nguyen

Xiong

et al. 2017

mBio

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“…Upon binding receptor, CdiA transfers its C-terminal toxin domain (CdiA-CT) into the target bacterium through an incompletely understood translocation mechanism (4,5). Genome and protein database surveys show that CdiA effectors carry a wide variety of distinct toxins (1,(6)(7)(8). CDI + cells protect themselves from self-intoxication by producing CdiI immunity proteins, which bind specifically to cognate CdiA-CT domains and neutralize their toxic activities.…”

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confidence: 99%

Activation of contact-dependent antibacterial tRNase toxins by translation elongation factors

Jones

Garza-Sánchez

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Contact-dependent growth inhibition (CDI) is a mechanism by which bacteria exchange toxins via direct cell-to-cell contact. CDI systems are distributed widely among Gram-negative pathogens and are thought to mediate interstrain competition. Here, we describe tsf mutations that alter the coiled-coil domain of elongation factor Ts (EF-Ts) and confer resistance to the CdiA-CT EC869 tRNase toxin from enterohemorrhagic Escherichia coli EC869. Although EF-Ts is required for toxicity in vivo, our results indicate that it is dispensable for tRNase activity in vitro. We find that CdiA-CT EC869 binds to elongation factor Tu (EF-Tu) with high affinity and this interaction is critical for nuclease activity. Moreover, in vitro tRNase activity is GTP-dependent, suggesting that CdiA-CT EC869 only cleaves tRNA in the context of translationally active GTP·EF-Tu·tRNA ternary complexes. We propose that EF-Ts promotes the formation of GTP·EF-Tu·tRNA ternary complexes, thereby accelerating substrate turnover for rapid depletion of target-cell tRNA.cell communication | protein synthesis | toxin-immunity proteins | ribonuclease | bacterial competition

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“…Thus, CDI is thought to mediate interstrain competition, with toxin/immunity protein variability providing a mechanism to discriminate between self and non-self (1,2).…”

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Unraveling the essential role of CysK in CDI toxin activation

Johnson

Beck

Morse

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Contact-dependent growth inhibition (CDI) is a widespread mechanism of bacterial competition. CDI + bacteria deliver the toxic C-terminal region of contact-dependent inhibition A proteins (CdiA-CT) into neighboring target bacteria and produce CDI immunity proteins (CdiI) to protect against self-inhibition. The CdiA-CT EC536 deployed by uropathogenic Escherichia coli 536 (EC536) is a bacterial toxin 28 (Ntox28) domain that only exhibits ribonuclease activity when bound to the cysteine biosynthetic enzyme O-acetylserine sulfhydrylase A (CysK). Here, we present crystal structures of the CysK/CdiA-CT EC536 binary complex and the neutralized ternary complex of CysK/CdiA-CT/ CdiI EC536 . CdiA-CT EC536 inserts its C-terminal Gly-Tyr-Gly-Ile peptide tail into the active-site cleft of CysK to anchor the interaction. Remarkably, E. coli serine O-acetyltransferase uses a similar Gly-Asp-Gly-Ile motif to form the "cysteine synthase" complex with CysK. The cysteine synthase complex is found throughout bacteria, protozoa, and plants, indicating that CdiA-CT EC536 exploits a highly conserved protein-protein interaction to promote its toxicity. CysK significantly increases CdiA-CT EC536 thermostability and is required for toxin interaction with tRNA substrates. These observations suggest that CysK stabilizes the toxin fold, thereby organizing the nuclease active site for substrate recognition and catalysis. By contrast, Ntox28 domains from Gram-positive bacteria lack C-terminal Gly-Tyr-Gly-Ile motifs, suggesting that they do not interact with CysK. We show that the Ntox28 domain from Ruminococcus lactaris is significantly more thermostable than CdiA-CT EC536 , and its intrinsic tRNA-binding properties support CysK-independent nuclease activity. The striking differences between related Ntox28 domains suggest that CDI toxins may be under evolutionary pressure to maintain low global stability.bacterial competition | structural biology | toxin chaperone | tRNase activity

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Contact-Dependent Growth Inhibition (CDI) and CdiB/CdiA Two-Partner Secretion Proteins

Cited by 91 publications

References 77 publications

CdiA Effectors Use Modular Receptor-Binding Domains To Recognize Target Bacteria

CdiA Effectors Use Modular Receptor-Binding Domains To Recognize Target Bacteria

Activation of contact-dependent antibacterial tRNase toxins by translation elongation factors

Unraveling the essential role of CysK in CDI toxin activation

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