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Lookup NU author(s): Dr Cecilia Piergentili, Professor Nigel Robinson
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The DUF156 family of DNA-binding transcriptional regulators includes metal sensors that respond to cobalt and/or nickel (RcnR, InrS) or copper (CsoR) plus CstR, which responds to persulfide, and formaldehyde-responsive FrmR. Unexpectedly, the allosteric mechanism of FrmR from Salmonella enterica serovar Typhimurium is triggered by metals in vitro, and variant FrmR(E64H) gains responsiveness to Zn(II) and cobalt in vivo Here we establish that the allosteric mechanism of FrmR is triggered directly by formaldehyde in vitro Sensitivity to formaldehyde requires a cysteine (Cys(35) in FrmR) conserved in all DUF156 proteins. A crystal structure of metal- and formaldehyde-sensing FrmR(E64H) reveals that an FrmR-specific amino-terminal Pro(2) is proximal to Cys(35), and these residues form the deduced formaldehyde-sensing site. Evidence is presented that implies that residues spatially close to the conserved cysteine tune the sensitivities of DUF156 proteins above or below critical thresholds for different effectors, generating the semblance of specificity within cells. Relative to FrmR, RcnR is less responsive to formaldehyde in vitro, and RcnR does not sense formaldehyde in vivo, but reciprocal mutations FrmR(P2S) and RcnR(S2P), respectively, impair and enhance formaldehyde reactivity in vitro Formaldehyde detoxification by FrmA requires S-(hydroxymethyl)glutathione, yet glutathione inhibits formaldehyde detection by FrmR in vivo and in vitro Quantifying the number of FrmR molecules per cell and modeling formaldehyde modification as a function of [formaldehyde] demonstrates that FrmR reactivity is optimized such that FrmR is modified and frmRA is derepressed at lower [formaldehyde] than required to generate S-(hydroxymethyl)glutathione. Expression of FrmA is thereby coordinated with the accumulation of its substrate.
Author(s): Osman D, Piergentili C, Chen J, Sayer LN, Usón I, Huggins TG, Robinson NJ, Pohl E
Publication type: Article
Publication status: Published
Journal: Journal of Biological Chemistry
Year: 2016
Volume: 291
Issue: 37
Pages: 19502-19516
Print publication date: 09/09/2015
Online publication date: 29/07/2016
Acceptance date: 15/07/2016
Date deposited: 14/10/2016
ISSN (print): 0021-9258
ISSN (electronic): 1083-351X
Publisher: American Society for Biochistry and Molecular Biology, Inc.
URL: http://dx.doi.org/10.1074/jbc.M116.745174
DOI: 10.1074/jbc.M116.745174
PubMed id: 27474740
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