InterPro domain: IPR036524

The eukaryotic proteins in this entry include frataxin, the protein that is mutated in Friedreich's ataxia [ 1 ], and related sequences. Friedreich's ataxia is a progressive neurodegenerative disorder caused by loss of function mutations in the gene encoding frataxin (FRDA). Frataxin mRNA is predominantly expressed in tissues with a high metabolic rate (including liver, kidney, brown fat and heart). Mouse and yeast frataxin homologues contain a potential N-terminal mitochondrial targeting sequence, and human frataxin has been observed to co-localise with a mitochondrial protein. Furthermore, disruption of the yeast gene has been shown to result in mitochondrial dysfunction. Friedreich's ataxia is thus believed to be a mitochondrial disease caused by a mutation in the nuclear genome (specifically, expansion of an intronic GAA triplet repeat) [ 2 , 3 , 4 ].

The bacterial proteins in this entry are iron-sulphur cluster (FeS) metabolism CyaY proteins homologous to eukaryotic frataxin. Partial Phylogenetic Profiling [ 5 ] suggests that CyaY most likely functions as part of the ISC system for FeS cluster biosynthesis, and is supported by expermimental data in some species [ 6 , 7 ].

The structure of Frataxin/CyaY has an alpha-beta(5)-alpha fold arranged in two layers (alpha/beta) with meander antiparallel sheet.

1. Friedreich's ataxia protein: phylogenetic evidence for mitochondrial dysfunction. Trends Neurosci. 19, 465-8
2. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423-7
3. Clinical and genetic abnormalities in patients with Friedreich's ataxia. N. Engl. J. Med. 335, 1169-75
4. Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat. Genet. 16, 345-51
5. Exopolysaccharide-associated protein sorting in environmental organisms: the PEP-CTERM/EpsH system. Application of a novel phylogenetic profiling heuristic. BMC Biol. 4, 29
6. Iron-sulfur cluster biosynthesis: characterization of Escherichia coli CYaY as an iron donor for the assembly of [2Fe-2S] clusters in the scaffold IscU. J. Biol. Chem. 281, 16256-63
7. Salmonella enterica strains lacking the frataxin homolog CyaY show defects in Fe-S cluster metabolism in vivo. J. Bacteriol. 188, 1175-9