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The Effectors and Sensory Sites of Formaldehyde-Responsive Regulator FrmR and Metal-Sensing Variant

Osman, Deenah; Piergentili, Cecilia; Chen, Junjun; Sayer, Lucy; Usón, Isabel; Huggins, Thomas; Robinson, Nigel; Pohl, Ehmke

The Effectors and Sensory Sites of Formaldehyde-Responsive Regulator FrmR and Metal-Sensing Variant Thumbnail


Deenah Osman

Cecilia Piergentili

Junjun Chen

Lucy Sayer

Isabel Usón

Thomas Huggins


The DUF156 family of DNA-binding, transcriptional-regulators include metal-sensors which 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 FrmRE64H 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 (Cys35 in FrmR) conserved in all DUF156 proteins. A crystal structure of metal- and formaldehyde-sensing FrmRE64H reveals that an FrmR-specific amino-terminal Pro2 is proximal to Cys35 and these residues form the deduced formaldehyde-sensing site. Evidence is presented which 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 FrmRP2S and RcnRS2P respectively impair or 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 modelling formaldehyde modification as a function of [formaldehyde], demonstrates that FrmR-reactivity is optimised such that FrmR is modified, and frmRA de-repressed, at lower [formaldehyde] than required to generate S-(hydroxymethyl)glutathione. Expression of FrmA is thereby coordinated with the accumulation of its substrate.


Osman, D., Piergentili, C., Chen, J., Sayer, L., Usón, I., Huggins, T., …Pohl, E. (2016). The Effectors and Sensory Sites of Formaldehyde-Responsive Regulator FrmR and Metal-Sensing Variant. Journal of Biological Chemistry, 291(37), 19502-19516.

Journal Article Type Article
Acceptance Date Jul 29, 2016
Online Publication Date Jul 29, 2016
Publication Date Sep 1, 2016
Deposit Date Aug 1, 2016
Publicly Available Date Aug 1, 2016
Journal Journal of Biological Chemistry
Print ISSN 0021-9258
Electronic ISSN 1083-351X
Publisher American Society for Biochemistry and Molecular Biology
Peer Reviewed Peer Reviewed
Volume 291
Issue 37
Pages 19502-19516
Public URL


Accepted Journal Article (1.4 Mb)

Copyright Statement
This final published version is available under a Creative Commons CC-BY license.

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