Crystal structure of human frataxin

Friedreich's ataxia, an autosomal recessive neurodegenerative disorder char acterized by progressive gait and limb ataxia, cardiomyopathy, and diabetes mellitus, is caused by decreased frataxin production or function. The stru cture of human frataxin, which we have determined at 1.8-Angstrom resolutio n, reveals a novel protein fold. A five-stranded, antiparallel beta sheet p rovides a flat platform, which supports a pair of parallel alpha helices, t o form a compact arp sandwich. A cluster of 12 acidic residues from the fir st helix and the first strand of the large sheet form a contiguous anionic surface on the protein. The overall protein structure and the anionic patch are conserved in eukaryotes, including animals, plants, and yeast, and in prokaryotes. Additional conserved residues create an extended 1008-Angstrom (2) patch on a distinct surface of the protein. Side chains of disease-asso ciated mutations either contribute to the anionic patch, help create the se cond conserved surface, or point toward frataxin's hydrophobic core. These structural findings predict potential modes of protein-protein and protein- iron binding.