Abstract
Frataxins form an interesting family of iron‐binding proteins with an almost unique fold and are highly conserved from bacteria to primates. They have a pivotal role in iron–sulfur cluster biogenesis as regulators of the rates of cluster formation, as it is testified by the fact that frataxin absence is incompatible with life and reduced levels of the protein lead to the recessive neurodegenerative disease Friedreich's ataxia. Despite its importance, the structure of frataxin has been solved only from relatively few species. Here, we discuss the X‐ray structure of frataxin from the thermophilic fungus Chaetomium thermophilum, and the characterization of its interactions and dynamics in solution. We show that this eukaryotic frataxin has an unusual variation in the classical frataxin fold: the last helix is shorter than in other frataxins which results in a less symmetrical and compact structure. The stability of this protein is comparable to that of human frataxin, currently the most stable among the frataxin orthologues. We also characterized the iron‐binding mode of Ct frataxin and demonstrated that it binds it through a semiconserved negatively charged ridge on the first helix and beta‐strand. Moreover, this frataxin is also able to bind the bacterial ortholog of the desulfurase, which is central in iron–sulfur cluster synthesis, and act as its inhibitor.
Highlights
Iron-sulfur clusters are inorganic cofactors thought to be present already in the protocell and to have provided the most ancient response to the problem of storing the toxic and yet essential iron and sulfur elements in living cells [1]
They have a pivotal role in iron-sulfur cluster biogenesis as regulators of the rates of cluster formation, as it is testified by the fact that frataxin absence is incompatible with life and reduced levels of the protein lead to the recessive neurodegenerative disease Friedreich’s ataxia
Since the affinity to iron is in the micromolar range and we do not know the exact stoichiometry because the binding is purely electrostatic, we used an excess of calcium
Summary
Iron-sulfur clusters are inorganic cofactors thought to be present already in the protocell and to have provided the most ancient response to the problem of storing the toxic and yet essential iron and sulfur elements in living cells [1] In proteins, they are usually coordinated by cysteine and/or histidine residues. Iron-sulfur clusters act as sulfur donors in biotin and lipoic acid cofactor biosynthesis Their synthesis and assembly into the target proteins is a complex and tightly regulated process under the control of evolutionary conserved machines, which were all discovered around year 2000 [4,5]. Frataxin is a highly conserved iron binding protein that is present both in prokaryotes and eukaryotes It regulates the rates of cluster formation and possibly acts as an iron donor through an interaction with the two central components of ironsulfur cluster formation, the desulfurase and the scaffold protein [10]. The surface of interaction with the desulfurase involves a semi-conserved negatively charged ridge [11]
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