The role of FeS-glutaredoxins and their cofactors in diseases

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FeS cluster are cofactors bound by protein ligands, mainly cysteinyl and histidyl residues, and essential for enzymatic or biological activity of the respective proteins. These paradigms changed after the identification of FeS coordinating glutaredoxins (Grxs): Grxs coordinate FeS cluster between two monomers using two molecules of non-covalently bound glutathione and two protein thiols in the active site as ligands. FeS binding thus inhibits enzymatic activity as oxidoreductase. Following our identification of human Grx2 as the first FeS-Grx, numerous other Grxs in all kingdoms of life have been characterized as FeS coordinating proteins. Although several essential functions of FeS-Grxs have been identified, e.g. during vertebrate development, FeS cluster biosynthesis, and iron trafficking, the distinct molecular role of the coordinated cofactor remains largely unknown. In our proposed project we will investigate the role of Grx coordinated FeS cluster in two different diseases connected to disturbed iron homeostasis: multiple sclerosis and cardiac hypertrophy. We will combine in vitro techniques (biochemistry and a variety of spectroscopic methods) with ex vivo (primary cell cultures, organotypic slice cultures) and in vivo models (animal models for multiple sclerosis, cardiac hypertrophy, and iron overload) as well as patient material. To reach our goals, we can refer to our well documented expertise in Grxs in general, and structure/function relationship of FeS-Grxs in particular. This knowledge provided the base for the construction of specific mutated forms of Grxs that differ in their ability to coordinate the FeS cluster and their enzymatic activity. Using these mutated Grxs we were already able to demonstrate nitric oxide detoxification as new function of Grx coordinated FeS cluster. The in-depth characterization of the nitric oxide-dependent disassembly of holo-Grxs will be one of the emphases of our project, the first comprehensive investigation of the role of FeS cluster coordinated by mammalian Grxs. The increasing importance of this protein family in FeS research is emphasised by the substantial network of applications to the priority program 1927 that address FeS-Grxs.