5hkq

Structural highlights

Function

CDIA_ECOST Toxic component of a toxin-immunity protein module, which functions as a cellular contact-dependent growth inhibition (CDI) system. CDI modules allow bacteria to communicate with and inhibit the growth of closely related neighboring target bacteria in a contact-dependent fashion (target cell counts decrease 1000- to 10000-fold with this CDI) (PubMed:28351921, PubMed:29923643). Uses outer membrane nucleoside transporter Tsx on target cells as a receptor (PubMed:28351921). Gains access to the cytoplasm of target cells by using integral inner membrane protein PTS system glucose-specific EIICB component (ptsG) (Probable). Targeting of the C-terminal domain (CT) domain (residues 2931-3253) in the absence of immunity protein inhibits cell growth and causes tRNA(UUC-Glu) cleavage; expression of cognate immunity protein CdiI-STECO31 neutralizes growth inhibition leaving tRNA(UUC-Glu) is intact, whereas non-cognate immunity proteins do not confer protection (PubMed:29923643). The CT domain cleaves tRNA; it is most active against tRNA(UUC-Glu), but also has modest activity against tRNA(GUC-Asp), tRNA(UUG-Gln), tRNA(CCC-Gly), tRNA(UCC-Gly), tRNA(GCC-Gly), tRNA(UUU-Lys), tRNA(GGU-Thr) and tRNA(CCA-Trp); tRNA cleavage is inhibited by cognate immunity protein CdiI. Cleavage of tRNA(UUC-Glu) occurs in the anticodon loop between cytosine(37) and 2-methyladenosine(38) (C37-m2A38) and probably also occurs in the anticodon loop of other tRNAs as well (PubMed:29923643).^{[1] [2] [3]} The CdiA protein is thought to be exported from the cell through the central lumen of CdiB, the other half of its two-partner system (TPS). The TPS domain probably remains associated with CdiB while the FHA-1 domain forms an extended filament (33 nm long) with the receptor-binding domain (RBD) at its extremity; in the secretion arrested state the C-terminus of the RBD and YP domains form a hairpin-like structure as the FHA-2, PT and CT domains are periplasmic. The YP domain is probably responsible for this arrest at the point where it re-enters the host cell periplasm. Upon binding to a target cell outer membrane receptor (Tsx for this CDI) a signal is transmitted to activate secretion. The filament becomes about 5 nm longer, the rest of CdiA is secreted and the FHA-2 domain becomes stably associated with the target cell's outer membrane where it facilitates entry of the toxic CT domain into the target cell periplasm. From there the toxic CT domain is cleaved and gains access to the target cell cytoplasm via an inner membrane protein (PTS system glucose-specific EIICB component, ptsG for this CDI).^[4]

References

1. ↑ Ruhe ZC, Nguyen JY, Xiong J, Koskiniemi S, Beck CM, Perkins BR, Low DA, Hayes CS. CdiA Effectors Use Modular Receptor-Binding Domains To Recognize Target Bacteria. mBio. 2017 Mar 28;8(2):e00290-17. PMID:28351921 doi:10.1128/mBio.00290-17
2. ↑ Michalska K, Quan Nhan D, Willett JLE, Stols LM, Eschenfeldt WH, Jones AM, Nguyen JY, Koskiniemi S, Low DA, Goulding CW, Joachimiak A, Hayes CS. Functional plasticity of antibacterial EndoU toxins. Mol Microbiol. 2018 Aug;109(4):509-527. doi: 10.1111/mmi.14007. Epub 2018 Aug 12. PMID:29923643 doi:http://dx.doi.org/10.1111/mmi.14007
3. ↑ Ruhe ZC, Nguyen JY, Xiong J, Koskiniemi S, Beck CM, Perkins BR, Low DA, Hayes CS. CdiA Effectors Use Modular Receptor-Binding Domains To Recognize Target Bacteria. mBio. 2017 Mar 28;8(2):e00290-17. PMID:28351921 doi:10.1128/mBio.00290-17
4. ↑ Ruhe ZC, Subramanian P, Song K, Nguyen JY, Stevens TA, Low DA, Jensen GJ, Hayes CS. Programmed Secretion Arrest and Receptor-Triggered Toxin Export during Antibacterial Contact-Dependent Growth Inhibition. Cell. 2018 Nov 1;175(4):921-933.e14. PMID:30388452 doi:10.1016/j.cell.2018.10.033
5. ↑ Michalska K, Quan Nhan D, Willett JLE, Stols LM, Eschenfeldt WH, Jones AM, Nguyen JY, Koskiniemi S, Low DA, Goulding CW, Joachimiak A, Hayes CS. Functional plasticity of antibacterial EndoU toxins. Mol Microbiol. 2018 Aug;109(4):509-527. doi: 10.1111/mmi.14007. Epub 2018 Aug 12. PMID:29923643 doi:http://dx.doi.org/10.1111/mmi.14007