Understanding the molecular machine that assembles essential iron-sulfur cluster cofactors

LEBRUN_U23DTP

Iron-sulfur (FeS) clusters are inorganic cofactors of proteins that are widely distributed in all types of cells where they function in electron transfer, catalysis and as sensors in multiple essential processes such as respiration, photosynthesis and nucleic acid metabolism.

They do not form spontaneously in cells and thus must be assembled. This must occur in a regulated way because iron and sulfur, though essential for life, are also intrinsically toxic. Nature has thus evolved highly complex and tightly regulated molecular machines for FeS biogenesis, which are evolutionarily conserved across the kingdoms of life, and all discovered within the past ~20 years.

The importance of these machines for human life is illustrated by the number of diseases that increasingly appear to be linked to impairment of iron-sulfur cluster proteins and their formation. When any of the parts of these machines break down, disease occurs.

Our understanding of FeS assembly in humans and bacteria is increasingly sophisticated, but there remains much to learn.

Understanding the steps involved in formation of clusters is limited by the lack of detailed information on the precise sequence of events and nature of intermediates, which interactions are formed and how they regulate thie overall process.

The Le Brun lab at UEA has recently shown that mass spectrometry under native conditions is extremely useful for studies of FeS cluster proteins.
This protein biochemistry project will utilise a range of techniques, including native mass spectrometry, to provide new insight into the steps of bacterial FeS cluster biogenesis.

This multi-disciplinary project offers excellent training potential for the appointed student within a supportive and stimulating environment.
Informal enquiries to Prof Nick Le Brun (n.le-brun@uea.ac.uk) are welcome.

References

1. Crack, J. C., Thomson, A. J. and Le Brun, N. E. (2017) Mass spectrometric identification of intermediates in the O2 driven [4Fe-4S] to [2Fe-2S] cluster conversion in FNR. Proc. Natl. Acad. Sci. U.S.A. 114, E3215-E3223. DOI: 10.1073/pnas.1620987114.

2. Pellicer Martinez, M. T., Crack, J. C., Stewart, M. Y. Y., Bradley, J. M., Svistunenko, D. A., Johnston, A. W. B., Cheesman, M. R., Todd, J. D., and Le Brun, N. E. (2019) Mechanism of iron- and O2-sensing by the [4Fe-4S] cluster of the global iron regulator RirA. eLife. 8, e47804. DOI: 10.7554/eLife.47804.

3. Volbeda, A., Pellicer Martinez, M. T., Crack, J. C., Amara, P., Gigarel, O., Munnoch, J. T., Huttchings, M. I., Darnault, C., Le Brun, N. E. and Fontecilla-Camps, J. C. (2019) The crystal structure of the transcription regulator RsrR reveals a [2Fe-2S] cluster coordinated by Cys, Glu and His residues. J. Am. Chem. Soc. 141, 2367-2375.

4. Crack, J. C. and Le Brun, N. E. (2021) Biological iron-sulfur clusters: mechanistic insights from mass spectrometry. Coord. Chem. Rev. 448, 214171.

5. Ebrahimi, K. H., Ciofi-Baffoni, S, Hagedoorn, P.-L., Nicolet, Y. Le Brun, N. E., Hagen, W. R., and Armstrong, F. A (2022) Iron-sulphur clusters as inhibitors and catalysts of viral replication. Nat. Chem. 14, 253-266.