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

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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.