The O2 sensitivity of the transcription factor FNR is controlled by Ser24 modulating the kinetics of [4Fe-4S] to [2Fe-2S] conversion

Jervis, Adrian J., Crack, Jason C., White, Gaye, Artymiuk, Peter J., Cheesman, Myles R., Thomson, Andrew J., Le Brun, Nick E. ORCID: https://orcid.org/0000-0001-9780-4061 and Green, Jeffrey (2009) The O2 sensitivity of the transcription factor FNR is controlled by Ser24 modulating the kinetics of [4Fe-4S] to [2Fe-2S] conversion. Proceedings of the National Academy of Sciences of the United States of America, 106 (12). pp. 4659-4664. ISSN 1091-6490

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Abstract

Fumarate and nitrate reduction regulatory (FNR) proteins are bacterial transcription factors that coordinate the switch between aerobic and anaerobic metabolism. In the absence of O2, FNR binds a [4Fe-4S]2+ cluster (ligated by Cys-20, 23, 29, 122) promoting the formation of a transcriptionally active dimer. In the presence of O2, FNR is converted into a monomeric, non-DNA-binding form containing a [2Fe-2S]2+ cluster. The reaction of the [4Fe-4S]2+ cluster with O2 has been shown to proceed via a 2-step process, an O2-dependent 1-electron oxidation to yield a [3Fe-4S]+ intermediate with release of 1 Fe2+ ion, followed by spontaneous rearrangement to the [2Fe-2S]2+ form with release of 1 Fe3+ and 2 S2- ions. Here, we show that replacement of Ser-24 by Arg, His, Phe, Trp, or Tyr enhances aerobic activity of FNR in vivo. The FNR-S24F protein incorporates a [4Fe-4S]2+ cluster with spectroscopic properties similar to those of FNR. However, the substitution enhances the stability of the [4Fe-4S]2+ cluster in the presence of O2. Kinetic analysis shows that both steps 1 and 2 are slower for FNR-S24F than for FNR. A molecular model suggests that step 1 of the FNR-S24F iron–sulfur cluster reaction with O2 is inhibited by shielding of the iron ligand Cys-23, suggesting that Cys-23 or the cluster iron bound to it is a primary site of O2 interaction. These data lead to a simple model of the FNR switch with physiological implications for the ability of FNR proteins to operate over different ranges of in vivo O2 concentrations.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Chemistry Faculty of Science > School of Biological Sciences
Depositing User:	Rachel Smith
Date Deposited:	23 Mar 2011 11:20
Last Modified:	23 Oct 2022 01:52
URI:	https://ueaeprints.uea.ac.uk/id/eprint/26984
DOI:	10.1073/pnas.0804943106

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