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Published online on January 31, 2007, 10.1073/pnas.0609514104
PNAS | February 13, 2007 | vol. 104 | no. 7 | 2092-2097


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BIOLOGICAL SCIENCES / PHYSICAL SCIENCES / BIOCHEMISTRY / CHEMISTRY
Superoxide-mediated amplification of the oxygen-induced switch from [4Fe-4S] to [2Fe-2S] clusters in the transcriptional regulator FNR

Jason C. Crack*, Jeffrey Green{dagger}, Myles R. Cheesman*, Nick E. Le Brun*,{ddagger}, and Andrew J. Thomson*,{ddagger}

*Centre for Metalloprotein Spectroscopy and Biology, School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom; and {dagger}Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield S10 2TN, United Kingdom

Edited by Harry B. Gray, California Institute of Technology, Pasadena, CA, and approved December 11, 2006 (received for review October 26, 2006)

In Escherichia coli, the switch between aerobic and anaerobic metabolism is controlled primarily by FNR (regulator of fumarate and nitrate reduction), the protein that regulates the transcription of >100 genes in response to oxygen. Under oxygen-limiting conditions, FNR binds a [4Fe-4S]2+ cluster, generating a transcriptionally active dimeric form. Upon exposure to oxygen the cluster converts to a [2Fe-2S]2+ form, leading to dissociation of the protein into monomers, which are incapable of binding DNA with high affinity. The mechanism of cluster conversion together with the nature of the products of conversion is of considerable current interest. Here, we demonstrate that [4Fe-4S]2+ to [2Fe-2S]2+ cluster conversion, in both native and reconstituted [4Fe-4S] FNR, proceeds via a one electron oxidation of the cluster, to give a [3Fe-4S]1+ cluster intermediate, with the release of one Fe2+ ion and a superoxide ion. The cluster intermediate subsequently rearranges spontaneously to form the [2Fe-2S]2+ cluster, with the release of a Fe3+ ion and, as previously shown, two sulfide ions. Superoxide ion undergoes dismutation to hydrogen peroxide and oxygen. This mechanism, a one electron activation of the cluster, coupled to catalytic recycling of the resulting superoxide ion back to oxygen, provides a means of amplifying the sensitivity of [4Fe-4S] FNR to its signal molecule.

DNA regulation | iron-sulfur

Author contributions: J.C.C., J.G., M.R.C., N.E.L.B., and A.J.T. designed research; J.C.C. performed research; J.C.C. and N.E.L.B. analyzed data; and J.C.C., J.G., N.E.L.B., and A.J.T. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS direct submission.

{ddagger}To whom correspondence may be addressed. E-mail: a.thomson{at}uea.ac.uk or n.le-brun{at}uea.ac.uk

© 2007 by The National Academy of Sciences of the USA


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