title: The phylogenetic distribution of frataxin indicates a role in iron-sulfur cluster protein assembly.
abstract: Much has been learned about the cellular pathology of Friedreich's ataxia, a recessive neurodegenerative disease resulting from insufficient expression of the mitochondrial protein frataxin. However, the biochemical function of frataxin has remained obscure, hampering attempts at therapeutic intervention. To predict functional interactions of frataxin with other proteins we investigated whether its gene specifically co-occurs with any other genes in sequenced genomes. In 56 available genomes we identified two genes with identical phylogenetic distributions to the frataxin/cyaY gene: hscA and hscB/JAC1. These genes have not only emerged in the same evolutionary lineage as the frataxin gene, they have also been lost at least twice with it, and they have been horizontally transferred with it in the evolution of the mitochondria. The proteins encoded by hscA and hscB, the chaperone HSP66 and the co-chaperone HSP20, have been shown to be required for the synthesis of 2Fe-2S clusters on ferredoxin in proteobacteria. JAC1, an ortholog of hscB, and SSQ1, a paralog of hscA, have been shown to be required for iron-sulfur cluster assembly in mitochondria of Saccharomyces cerevisiae. Combining data on the co-occurrence of genes in genomes with experimental and predicted cellular localization data of their proteins supports the hypothesis that frataxin is directly involved in iron-sulfur cluster protein assembly. They indicate that frataxin is specifically involved in the same sub-process as HSP20/Jac1p.
authors.affiliation: Biocomputing, EMBL/Max-Delbrueck-Center fur molecular medicin, Berlin-Buch, Germany. huynen@cmbi.kun.nl
authors.forename: M A
authors.initials: MA
authors.lastname: Huynen
authors.forename: B
authors.initials: B
authors.lastname: Snel
authors.forename: P
authors.initials: P
authors.lastname: Bork
authors.forename: T J
authors.initials: TJ
authors.lastname: Gibson
mesh_terms: D000818:Animals; D001419:Bacteria / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D020635:Buchnera / Q000235:genetics / Q000378:metabolism; D005057:Eukaryotic Cells / Q000378:metabolism; D019143:Evolution, Molecular; D016678:Genome; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D010802:Phylogeny; D011485:Protein Binding; D029701:Saccharomyces cerevisiae Proteins; D000096923:Frataxin
chemical_list: D001426:Bacterial Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D033862:Iron-Binding Proteins; D007506:Iron-Sulfur Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D017853:Phosphotransferases (Alcohol Group Acceptor); D029701:Saccharomyces cerevisiae Proteins; D000096923:Frataxin; C115914:JAC1 protein, S cerevisiae; C115913:SSQ1 protein, S cerevisiae