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. 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.

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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: 27 Apr 2022 04:35
DOI: 10.1073/pnas.0804943106

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