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Intramolecular Interactions Dominate the Autoregulation of Escherichia coli Stringent Factor RelA
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Centre for Bacterial Stress Response and Persistence, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Institute of Technology, University of Tartu, Tartu, Estonia.
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2019 (English)In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 10, article id 1966Article in journal (Refereed) Published
Abstract [en]

Amino acid starvation in Escherichia coli activates the enzymatic activity of the stringent factor RelA, leading to accumulation of the alarmone nucleotide (p)ppGpp. The alarmone acts as an intercellular messenger to regulate transcription, translation and metabolism to mediate bacterial stress adaptation. The enzymatic activity of RelA is subject to multi-layered allosteric control executed both by ligands - such as "starved" ribosomal complexes, deacylated tRNA and pppGpp - and by individual RelA domains. The auto-regulation of RelA is proposed to act either in cis (inhibition of the enzymatic activity of the N-terminal region, NTD, by regulatory C-terminal region, CTD) or in trans (CTD-mediated dimerization leading to enzyme inhibition). In this report, we probed the regulatory roles of the individual domains of E. coli RelA and our results are not indicative of RelA dimerization being the key regulatory mechanism. First, at growth-permitting levels, ectopic expression of RelA CTD does not interfere with activation of native ReIA, indicating lack of regulation via inhibitory complex formation in the cell. Second, in our biochemical assays, increasing RelA concentration does not decrease the enzyme activity, as would be expected in the case of efficient auto-inhibition via dimerization. Third, while high-level CTD expression efficiently inhibits the growth, the effect is independent of native RelA and is mediated by direct inhibition of protein synthesis, likely via direct interaction with the ribosomal A-site. Finally, deletion of the RRM domain of the CTD region leads to growth inhibition mediated by accumulation of (p)ppGpp, suggesting de-regulation of the synthetic activity in this mutant.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2019. Vol. 10, article id 1966
Keywords [en]
(p)ppGpp, RelA, RSH, stringent response, ribosome, translation
National Category
Biochemistry and Molecular Biology Medical Biotechnology
Identifiers
URN: urn:nbn:se:umu:diva-163667DOI: 10.3389/fmicb.2019.01966ISI: 000482805400001OAI: oai:DiVA.org:umu-163667DiVA, id: diva2:1362852
Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2019-10-21Bibliographically approved

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Turnbull, Kathryn JaneDzhygyr, IevgenHauryliuk, VasiliRoghanian, Mohammad
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