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Structural insights into CodY activation and DNA recognition
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). (Sauer-Eriksson)ORCID iD: 0000.0001.7282.1789
Umeå University, Faculty of Science and Technology, Department of Chemistry. QureTech Bio, Umeå, Sweden.ORCID iD: 0000-0003-4624-4337
Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0003-4646-0216
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, Umeå Centre for Microbial Research (UCMR).ORCID iD: 0000-0002-0904-497x
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2023 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 51, no 14, p. 7631-7648Article in journal, Letter (Refereed) Published
Abstract [en]

Virulence factors enable pathogenic bacteria to infect host cells, establish infection, and contribute to disease progressions. In Gram-positive pathogens such as Staphylococcus aureus (Sa) and Enterococcus faecalis (Ef), the pleiotropic transcription factor CodY plays a key role in integrating metabolism and virulence factor expression. However, to date, the structural mechanisms of CodY activation and DNA recognition are not understood. Here, we report the crystal structures of CodY from Sa and Ef in their ligand-free form and their ligand-bound form complexed with DNA. Binding of the ligands - branched chain amino acids and GTP - induces conformational changes in the form of helical shifts that propagate to the homodimer interface and reorient the linker helices and DNA binding domains. DNA binding is mediated by a non-canonical recognition mechanism dictated by DNA shape readout. Furthermore, two CodY dimers bind to two overlapping binding sites in a highly cooperative manner facilitated by cross-dimer interactions and minor groove deformation. Our structural and biochemical data explain how CodY can bind a wide range of substrates, a hallmark of many pleiotropic transcription factors. These data contribute to a better understanding of the mechanisms underlying virulence activation in important human pathogens.

Place, publisher, year, edition, pages
Oxford University Press, 2023. Vol. 51, no 14, p. 7631-7648
Keywords [en]
CodY, virulence, protein-DNA complex structure
National Category
Biochemistry and Molecular Biology Bioinformatics and Systems Biology
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:umu:diva-214131DOI: 10.1093/nar/gkad512ISI: 001008706900001Scopus ID: 2-s2.0-85168963845OAI: oai:DiVA.org:umu-214131DiVA, id: diva2:1794435
Projects
CodY
Funder
Swedish Research Council, ID 2019-03771Swedish Research Council, 2020-02005_3 toSwedish Research Council, 2018-04589Swedish Research Council, 2021-05040JAvailable from: 2023-09-05 Created: 2023-09-05 Last updated: 2023-09-05Bibliographically approved

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Hainzl, TobiasBonde, MariAlmqvist, FredrikJohansson, JörgenSauer-Eriksson, A. Elisabeth

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Hainzl, TobiasBonde, MariAlmqvist, FredrikJohansson, JörgenSauer-Eriksson, A. Elisabeth
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Department of ChemistryUmeå Centre for Microbial Research (UCMR)Department of Molecular Biology (Faculty of Medicine)Molecular Infection Medicine Sweden (MIMS)
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Nucleic Acids Research
Biochemistry and Molecular BiologyBioinformatics and Systems Biology

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