Towards a structural understanding of Friedreich's ataxia: the solution structure of frataxin

Background: Lesions in the gene for frataxin, a nuclear-encoded mitochondri al protein, cause the recessively inherited condition Friedreich's ataxia. It is thought that the condition arises from disregulation of mitochondrial iron homeostasis, with concomitant oxidative damage leading to neuronal de ath. Very little is, as yet, known about the biochemical function of fratax in. Results: Here, we show that the mature form of recombinant frataxin behaves in solution as a monodisperse species that is composed of a 15-residue-lon g unstructured N terminus and an evolutionarily conserved C-terminal region that is able to fold independently. The structure of the C-terminal domain consists of a stable seven-stranded antiparallel beta sheet packing agains t a pair of parallel helices. The structure is compact with neither grooves nor cavities, features that are typical of iron-binding modules. Exposed e volutionarily conserved residues cover a broad area and all cluster on the beta-sheet face of the structure, suggesting that this is a functionally im portant surface. The effect of two clinically occurring mutations on the fo ld was checked experimentally. When the mature protein was titrated with ir on, no tendency to iron-binding or to aggregation was observed. Conclusions: Knowledge of the frataxin structure provides important guideli nes as to the nature of the frataxin binding partner, The absence of all th e features expected for an iron-binding activity, the large conserved area on its surface and lack of evidence for iron-binding activity strongly supp ort an indirect involvement of frataxin in iron metabolism. The effects of point mutations associated with Friedreich's ataxia can be rationalised by knowledge of the structure and suggest possible models for the occurrence o f the disease in compound heterozygous patients.