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Structural basis for kinase inhibition in the tripartite E. coli HipBST toxin-antitoxin system
Open accessPreprint — published as 10.7554/elife.90400.3 · Paper page
Abstract
Abstract Many bacteria encode multiple toxin-antitoxin (TA) systems targeting separate, but closely related, cellular functions. The toxin of the E. coli hipBA system, HipA, is a kinase that inhibits translation via phosphorylation of glutamyl-tRNA synthetase. Enteropathogenic E. coli (EPEC) O127:H6 encodes the hipBA-like, tripartite TA system; hipBST, in which the HipT toxin specifically targets the tryptophanyl-tRNA synthetase, TrpS. Notably, in the tripartite system, the function as antitoxin has been taken over by the third protein, HipS, but the molecular details of how activity of HipT is inhibited remain poorly understood. Here, we show that HipBST is structurally different from E. coli HipBA and that the unique HipS protein, which is homologous to the N-terminal subdomain of HipA, inhibits the kinase through insertion of a conserved Trp residue into the active site. We also show how auto-phosphorylation at two conserved sites in the kinase toxin serve different roles and affect the ability of HipS to neutralize HipT. Finally, solution structural studies show how phosphorylation affects overall TA complex flexibility.
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Metadata
- Authors
- Bærentsen, R. L., Nielsen, S. V., Skjerning, R. B., Lyngsø, J., Bisiak, F., Pedersen, J. S., Gerdes, K., Sørensen, M. A., & Brodersen, D. E.
- Affiliations
- Aarhus University (DK)
- University of Copenhagen (DK)
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2023-10-12
- ISSN
- 2050-084X (ISSN-L)
- OpenAlex
- W4387578681
- Cited by
- 1
- References
- 44
- Citations by year
- 2025: 1
- Type
- posted content
- Language
- en
- Open access
- gold
- doi.org
- Locations
- eLife (acceptedVersion, cc-by)
- Funders
- Novo Nordisk Foundation (NNF18OC0030646)
- Danmarks Grundforskningsfond (DNRF120)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
- Keywords
- toxin-antitoxin systems, tryptophanyl-tRNA synthetase, glutamyl-tRNA synthetase, protein synthesis inhibition, kinase inhibition, autophosphorylation, Escherichia coli
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