Iron storage and detoxification in human ferritins

LEBRUN_U21DTP1

Iron is an essential micronutrient for life, but its reactivity also means that it is potentially extremely toxic, and uncontrolled reactions with O2 can generate reactive oxygen species, which cause cellular damage and death. Indeed, breakdown in cellular iron metabolism is linked, directly or indirectly, to many disease states. Thus, organisms/cells must carefully regulate the amount and form of iron. This is, in part, achieved through storage of iron as a ferric mineral solubilised within ferritin proteins, which are found in all types of cells, from bacteria to humans.

Ferritins are composed of 24 subunits arranged in a highly symmetric fashion to form a football-shaped molecule, in which a rust-like iron mineral is formed and solubilised. Animal ferritins are composed of a mixture of two types of subunits, H-chain and L-chain, and the H-chain type contains an active site that catalyses the formation of the mineral. The aim of the project is to understand how human ferritins store/detoxify iron, and what the consequences of variable H/L subunit proportions are for this mechanism. New fundamental insight gained through the project will impact on understanding of human cellular iron metabolism and its importance for health.

This multi-disciplinary project will be based in the Le Brun lab at UEA, and will involve protein purification, biochemistry, mass spectrometry, spectroscopy, crystallography and rapid kinetic methods, offering 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:

Bradley, J. M., Pullin, J., Moore, G. R., Svistunenko, D. A., Hemmings, A. M. and Le Brun, N. E. (2019) Routes of iron entry into, and exit from, the catalytic ferroxidase sites of the prokaryotic ferritin SynFtn. Dalton Trans., 49, 1545 – 1554.

Bradley, J. M., Svistunenko, D. A., Pullin, J., Hill, N., Stuart, R. K., Palenik, B., Wilson, M. T., Hemmings, A. M., Moore, G. R. and Le Brun, N. E. (2019) Reaction of O2 with a di-iron protein generates a mixed valent Fe2+/Fe3+ center and peroxide. Proc. Natl. Acad. Sci. U.S.A., 116, 2058-2067.

Bradley, J. M., Svistunenko, D. A., Moore, G. R. and Le Brun, N. E. (2017) Tyr25, Tyr58 and Trp133 of Escherichia coli bacterioferritin transfer electrons between iron in the central cavity and the ferroxidase centre. Metallomics 9, 1421-1428.