Chaperone Function in Iron-Sulfur Protein Folding

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DESCRIPTION (provided by applicant): Proteins containing iron-sulfur clusters possess important electron transfer, catalytic, and regulatory functions, but the cellular mechanisms by which the Fe-S clusters are formed and introduced into proteins are not well understood. Recent studies have identified novel proteins that participate in Fe-S protein biosynthesis, and their roles and interactions are being defined. In bacteria several of these proteins are encoded in a conserved gene cluster that encodes three Fe-S cluster assembly components (IscS, IscU, IscA), and a specialized chaperone/co-chaperone system (HscA and HscB). We have produced recombinant forms of each of these proteins from Escherichia coli, and propose biochemical, biophysical and structural studies to investigate their roles in the assembly of Fe-S-clusters and the incorporation of Fe-S clusters into proteins. The proposed studies will address 1) the mechanism of transfer of sulfur from the cysteine desulfurase IscS to the transient Fe-S scaffold protein IscU, 2) the role of IscA in iron binding and cluster assembly, 3) interactions of IscU with the HscA/HscB chaperone system, and 4) the transfer of Fe-S clusters to acceptor apo-proteins. Additional studies on the interaction of HscA with peptides will also be carried out to investigate general principles of hsp70-substrate interactions. Results of these studies will provide a better understanding of molecular mechanisms involved in the biogenesis of Fe-S proteins. Furthermore, a similar conserved mechanism of Fe-S protein assembly occurs in eukaryotes, and the findings may provide insight into the molecular basis of human diseases such as those associated with mitochondrial myopathies.