Molecular mechanism and structure of the cytosolic iron-sulfur protein assembly (CIA) machinery

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Iron-sulfur (Fe/S) clusters are essential protein cofactors involved in numerous key biological processes such as metabolism, energy conversion, DNA synthesis and repair, and protein translation. The synthesis of Fe/S clusters and their insertion into target proteins in a living cell is catalyzed by complex machinery. In (non-green) eukaryotes three biogenesis systems have been identified in mitochondria and cytosol with more than 30 known components. Mitochondrial Fe/S proteins require the iron-sulfur cluster (ISC) assembly machinery which was inherited from bacteria during evolution. Biogenesis of cytosolic and nuclear Fe/S proteins also depends on the function of this machinery, yet additionally requires the mitochondrial ISC export apparatus and the cytosolic iron-sulfur protein assembly (CIA) machinery. Hitherto, eleven CIA proteins have been identified and their sequence of action been defined, yet little is known about their biochemical function. This proposal therefore aims to elucidate the molecular mechanisms of three CIA protein complexes. Cell biological and biochemical reconstitution approaches will be combined with ultrastructural und mutational techniques to define the molecular events of how a [4Fe-4S] cluster is initially synthesized on the CIA scaffold complex and then specifically inserted into target apoproteins via the CIA targeting and adapter complexes. Our studies will help resolving the sophisticated molecular mechanisms of a central and conserved process of life.