Human Molecular Genetics, 2001, Vol. 10, No. 21 2463-2468
© 2001 Oxford University Press
The phylogenetic distribution of frataxin indicates a role in iron-sulfur cluster protein assembly
Biocomputing, EMBL/Max-Delbrueck-Center fur molecular medicin, Berlin-Buch and 1Biocomputing, EMBL, Meyerhofstrasse 1, 69117 Heidelberg, Germany
Received July 3, 2001; Revised and Accepted July 30, 2001.
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ABSTRACT |
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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.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The sequencing of complete genomes has provided the opportunity not only to interpret the function of a protein within its proteomic context, but also to predict new functional interactions between proteins using comparative genome analysis (1). Specifically it has been proposed (2) and demonstrated (3) that proteins of genes that co-occur with each other in genomes (they are either both present or both absent) tend to functionally interact. The co-occurrence of genes in genomes (also called ‘phylogenetic profiles’) can be used as a tool to predict functional interactions between their proteins (4,5). Such functional interactions span a wide variation of interactions, including direct physical interactions between the proteins, but also less direct ones, such as being part of the same metabolic pathway or biological process (5). When there is prior knowledge about a protein’s involvement in a process, yet the exact function of the protein is not known, the co-occurrence of genes can more specifically pinpoint in which sub-process the protein plays a role (6,7). Here we use genome comparisons to predict functional interactions for frataxin, a mitochondrial protein that has no detectable homologs with known function and that presently has a unique fold (8,9). Severely reduced levels of frataxin cause the disease Friedreich’s ataxia (10), which is characterized by degeneration of large sensory neurons and spinocerebellar tracts, cardiomyopathy and increased likelihood of diabetes (11). In mitochondria, reduced levels of frataxin result in the absence of iron-sulfur cluster (isc) dependent enzymes, accumulation of iron deposits, DNA damage and oxidative stress (12). Based on such observations the main hypothesis about frataxin’s function is that it is directly involved in iron homeostasis of the mitochondria. Alternatively it has been proposed that frataxin is involved in isc assembly on iron-sulfur proteins (13). Recent findings that the yeast ortholog of frataxin precipitates with iron support the first hypothesis (14); however, they could not be reproduced with purified human frataxin itself (8). Here we show that the frataxin gene and its orthologs (cyaY in bacteria) have the same phylogenetic distribution as the chaperones hscA and hscB/JAC1, supporting a direct role in the assembly of isc proteins, rather than in iron homeostasis.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Co-occurrence of frataxin with proteins involved in isc assembly in the bacteria
Orthologs of the human frataxin gene are found in all sequenced eukaryotic genomes, and in most proteobacteria (purple bacteria), specifically in all but one of the sequenced
-proteobacteria, in all of the sequenced ß-proteobacteria and in one of the sequenced 
-proteobacteria: Rickettsia prowazekii, the closest fully sequenced relative to the ancestor of the mitochondria (Fig. 1). That frataxin is only present in the proteobacterial clade led to the proposal that in eukaryotes the protein is targeted to the mitochondrion (15), which was substantiated by subsequent experimental evidence (10,16–18).
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To find possible interaction partners for frataxin we determined the phylogenetic distribution of all genes of the smallest genome that contains the frataxin gene: the intracellular symbiont proteobacterium Buchnera (Materials and Methods). As summarized in Figure 1, only two genes have a phylogenetic distribution that is identical to that of frataxin: the chaperone pair hscA and hscB/JAC1 (Fig. 1). In bacteria this pair is part of the so-called isc assembly operon (19) that in Escherichia coli encodes nine proteins: a hypothetical RNA methylase (E.coli gene no. EC2532), a hypothetical helix–turn–helix containing transcriptional regulatory protein (EC2531), IscS, IscU, IscA, HscB, HscA, fdx (a 2Fe-2S ferredoxin), and a third hypothetical protein (EC2524). A number of the encoded proteins appear to be involved in the generation of iscs on ferredoxin in E.coli: IscS, IscA, HscA, HscB and EC2524 (20). The clustering of these genes into one operon (actually two operons in Rickettsia and Neisseria) has, within the bacteria, the same phylogenetic distribution as the frataxin gene. However, at the level of the individual genes this only applies to hscB and hscA. Other genes from the cluster are either more widespread in the bacteria (EC2532, EC2531, iscS, iscU, iscA and fdx) or less widespread (EC2524).
Evolution of the eukaryotic isc assembly in mitochondria
Eukaryotic orthologs, and in one case a paralog, of most of the bacterial isc proteins have been implicated in isc generation in yeast. These are: Nfs1p (21) (ortholog of IscS), Isu1p and Isu2p (22) (orthologs of IscU), Isa1p and Isa2p (23,24) (orthologs of IscA), Yah1p (25) (ortholog of the fdx gene product), Ssq1p (26) (paralog of HscA; see below and Fig. 2) and Jac1p (26,27) (ortholog of HscB). EC2532, EC2531 and EC2524 have no orthologs in the eukaryotes and appear not to have been part of the massive horizontal gene transfer that accompanied the origin of the mitochondria. Besides the frataxin ortholog Yfh1p, several other yeast proteins without orthologs in the bacterial isc operon have also been implicated in isc assembly. Nfu1p (22) and Atm1p (28) (an ABC transporter that exports the iscs from the mitochondria) have full-length orthologs in all the sequenced -proteobacteria, while the adrenodoxin/ferredoxin reductase Arh1p (29) has orthologs in some gram-positive bacteria. With a couple of exceptions the isc assembly proteins in mitochondria have thus been derived from the proteobacterial isc operon, implying a considerable conservation of the isc assembly from the proteobacteria to the mitochondria (22,30). Within the sequenced eukaryotes the isc set of proteins appears perfectly conserved; the yeast proteins implicated in isc assembly have orthologs in all the other sequenced eukaryotic genomes (Fig. 1), although some variation might exist in the compartmentalization of the isc assembly (31).
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A paralogous displacement in isc assembly in eukaryotes
Interestingly Ssq1p, the HSP70 protein that functions in the yeast mitochondrion in isc assembly, is not orthologous to HscA, but rather paralogous to it (Fig. 2). Orthologs of hscA are present in all sequenced eukaryotic genomes but their proteins have not been observed in mitochondria. In addition, the protein localization prediction program Psort (32) predicts the proteins of this orthologous group to be cytoplasmic. This switching of DnaK with HscA in the evolution of the eukaryotic cell suggests that the functioning of DnaK/HscA in isc assembly is not very substrate specific. It should be noted here that the substrate specificity of the DnaK-DnaJ pair is largely determined by DnaJ (33). Furthermore, in the evolution of HscA-HscB from DnaK-DnaJ, it is HscB that has undergone the largest change, having only retained the N-terminal, DnaK interacting domain from DnaJ, while the middle and C-terminal domains have been replaced by a heterologous three helix bundle domain (34). In contrast, HscA is a full length homolog of DnaK. It has retained functionality as a chaperone for standard substrates as such as rhodanese or citrate synthase (35). Relative to HscB, HscA has thus retained more of the structure and function of its ancestral protein. HscA might thus have been easier to replace by its ancestor DnaK than HscB by its ancestor DnaJ in the evolution of isc assembly. Note also that while in the fungi and in Arabidopsis there have been a number of gene duplications of the mitochondrial HSP70 proteins, leading for example to the three HSP70 proteins of this orthologous group in Saccharomyces cerevisiae—among which the functionally differentiated Ssq1p and Ssc1p, in the metazoa no such duplications can be detected. Homo sapiens has only one member of this orthologous group of proteins.
Co-evolution of the HscA, HscB and frataxin genes
Given their widespread phylogenetic distribution, EC2532, EC2531, iscS, iscU and fdx are likely to have existed in the bacteria before the dnaK-dnaJ duplication gave rise to hscA-hscB, apparently in the proteobacterial clade. At about the same time that frataxin was invented, this chaperone pair has thus been added to a preexisting set of isc proteins that are likely to have already functioned in isc assembly. Subsequently the hscA-hscB gene pair and frataxin have been lost in Xylella fastidiosa and in the lineage leading to Melorhizobium loti and Caulobacter crescentus (Fig. 1). Such co-loss of genes increases the likelihood that the proteins they encode are functionally linked (6,7). Furthermore, a large fraction of the set of isc genes have been transferred together with the frataxin gene to the nuclear genome of eukaryotes after the symbiosis of an -proteobacterium with the predecessor of the eukaryotes that led to the mitochondria. Note that one other gene has been invented at about the same time as hscA, hscB and frataxin/cyaY: iscA (through a gene duplication within the HesB family). However, its subsequent evolutionary history is different. For example, IscA has been lost from Buchnera while hscA, hscB and frataxin/cyaY have been retained in this species.
Molecular functions of the likely interaction partners of frataxin: HscA/Ssq1p and HscB/Jac1p
Based both on experimental evidence and on their phylogenetic distribution, the isc proteins can be divided into subsets. On the one hand IscS/Nfs1p, IscU/Isu1-2p and IscA/Isa1-2p function in the assembly of iron-clusters themselves. IscS/Nfs1 are cysteine desulfurases (21). IscU/Isu1-2p serve as scaffolds for isc biosynthesis (36). IscA has been shown to interact with the holoform of ferredoxin (37), and conserved, essential cysteines in Isa1p hint at a role in iron-binding (23). On the other hand, although HscA/Ssq1p and HscB/Jac1p have consistently been shown to be involved in the generation of iscs in bacteria and mitochondria (20,26,27), their exact molecular functions have not been elucidated. The homology of HscA/Ssq1p and HscB/Jac1p with the protein pair DnaK and DnaJ suggests that they function as chaperones, possibly facilitating the folding of iron-sulfur proteins. One substrate of the chaperone pair is IscU. Physical interaction between IscU and HscA/HscB has been observed in E.coli (38). HscA/HscB could serve as specialized chaperones for IscU (35), but might also facilitate the transfer of Fe/S clusters formed in IscU to apoacceptor proteins (35). While HscA is a full-length homolog of DnaK, HscB shares only the N-terminal, DnaK-binding domain with the classical DnaJ. In HscB, the zinc-finger middle domain and the C-terminal domain that in DnaJ are involved in substrate binding (39,40) have been replaced with a three helix bundle coiled-coil like structure (34), of which the function is not yet clear.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The identical phylogenetic distribution of the frataxin gene with hscA/SSQ1 and hscB/JAC1 suggests that frataxin plays a role in the same stage of the process of isc protein assembly as the HscA-HscB chaperone system, possibly as co-chaperone, or in protecting the sulfhydryl groups of iron-sulfur apoproteins. One possibility is that frataxin plays a role in the selection of the substrate. It could replace the substrate-selecting function of the middle and C-terminal domains of DnaJ that are missing in HscB/Jac1p. The conservation of a string of negatively charged residues on the surface of the protein (8) supports the hypothesis of a role in peptide binding. Alternatively it could interact with HscA/Ssq1p. However, the paralogous displacement of HscA with Ssq1p in the evolution of isc assembly makes this interaction less likely to be specific. Nevertheless, Ssq1p has been shown to be involved, together with Ssc1p, in the maturation of the yeast frataxin ortholog, Yfh1p (41). It should be noted that the types of functional interaction that correlate with the co-occurrence of genes in genomes include a large variation of functional interactions, and do not necessarily reflect physical interaction, but rather that the proteins are involved in the same (sub)process.
In any case, the strict co-occurrence of the frataxin gene with hscA/SSQ1 and hscB/JAC1 strongly supports a direct role of frataxin in isc protein assembly. The hypothesis that frataxin is directly involved in isc assembly and that the accumulation of iron in frataxin-deficient cells is only a secondary effect is not new (13). Recent evidence from yeast supports a direct role of frataxin in isc assembly (26), while in frataxin-deficient mouse cells the accumulation of iron is secondary to deficiency of isc proteins (42). Based on the co-occurrence of genes in genomes and their encoded proteins having the same distribution in the eukaryotic cell, we can, however, be more specific in our predictions: frataxin should function in conjunction with HscB/Jac1p.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The determination of orthology relations between the genes in Buchnera and the other 55 sequenced genomes was done in two steps. First we compared all the predicted protein sequences from Buchnera with those from the other genomes using the Smith–Waterman (43) algorithm and selected bidirectional best, not-overlapping (to include the possibility of fission/fusion of genes), homologs (E < 0.01) (1). This procedure gives a first-order approximation of the orthology relations. Subsequently the 20 genes that had the most similar phylogenetic distribution to that of the frataxin gene were selected for more careful, manual analysis. For those genes we performed iterative PSI-Blast searches (five iterations, E < 0.001) (44) to select all family members of these genes. These were aligned using clustalX (45) and Neighbor-joining trees were constructed (46). In the second step we made high quality orthology predictions by manual inspection of these phylogenetic trees. Subsequently groups of orthologous genes were selected that had the most similar distribution to the frataxin gene. This procedure revealed only two genes with the same distribution as frataxin, hscA and hscB/JAC1; other genes from Buchnera have a discrepancy of at least seven in their phylogenetic distribution, i.e. there are seven genomes where either they are present and frataxin is not, or vice versa. All sequenced prokaryotic genomes (for an overview see www.tigr.org/tdb/mdb/mdbcomplete.html) and those of S.cerevisiae, Drosophila melanogaster and Arabidopsis thaliana were obtained from GenBank (ftp.ncbi.nlm.nih.gov/pub/genomes). The Schizosaccharomyces pombe genome was obtained from the European Schizosaccharomyces genome sequencing project (http://www.sanger.ac.uk/Projects/S_pombe), Candida albicans from the Stanford Genome Technology Center (http://www-sequence.stanford.edu/group/candida/search. html) and the H.sapiens genome from Ensembl (http://www.ensembl.org).
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ACKNOWLEDGEMENTS |
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This research was supported by the BMBF. We thank the referees for their comments.
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FOOTNOTES |
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+ To whom correspondence should be addressed at: University Medical Center Nijmegen, p/a CMBI, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands. Tel: +31 24 3653374; Fax: +31 24 3652977; Email: huynen@cmbi.kun.nl
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G. Layer, S. Ollagnier-de Choudens, Y. Sanakis, and M. Fontecave 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., June 16, 2006; 281(24): 16256 - 16263. [Abstract] [Full Text] [PDF]
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 E. Vivas, E. Skovran, and D. M. Downs Salmonella enterica Strains Lacking the Frataxin Homolog CyaY Show Defects in Fe-S Cluster Metabolism In Vivo J. Bacteriol., February 1, 2006; 188(3): 1175 - 1179. [Abstract] [Full Text] [PDF]
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 F. Acquaviva, I. De Biase, L. Nezi, G. Ruggiero, F. Tatangelo, C. Pisano, A. Monticelli, C. Garbi, A. M. Acquaviva, and S. Cocozza Extra-mitochondrial localisation of frataxin and its association with IscU1 during enterocyte-like differentiation of the human colon adenocarcinoma cell line Caco-2 J. Cell Sci., September 1, 2005; 118(17): 3917 - 3924. [Abstract] [Full Text] [PDF]
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 H. Seznec, D. Simon, C. Bouton, L. Reutenauer, A. Hertzog, P. Golik, V. Procaccio, M. Patel, J.-C. Drapier, M. Koenig, et al. Friedreich ataxia: the oxidative stress paradox Hum. Mol. Genet., February 15, 2005; 14(4): 463 - 474. [Abstract] [Full Text] [PDF]
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J. J. Silberg, T. L. Tapley, K. G. Hoff, and L. E. Vickery Regulation of the HscA ATPase Reaction Cycle by the Co-chaperone HscB and the Iron-Sulfur Cluster Assembly Protein IscU J. Biol. Chem., December 24, 2004; 279(52): 53924 - 53931. [Abstract] [Full Text] [PDF]
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O. Stehling, H.-P. Elsasser, B. Bruckel, U. Muhlenhoff, and R. Lill Iron-sulfur protein maturation in human cells: evidence for a function of frataxin Hum. Mol. Genet., December 1, 2004; 13(23): 3007 - 3015. [Abstract] [Full Text] [PDF]
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 D. Simon, H. Seznec, A. Gansmuller, N. Carelle, P. Weber, D. Metzger, P. Rustin, M. Koenig, and H. Puccio Friedreich Ataxia Mouse Models with Progressive Cerebellar and Sensory Ataxia Reveal Autophagic Neurodegeneration in Dorsal Root Ganglia J. Neurosci., February 25, 2004; 24(8): 1987 - 1995. [Abstract] [Full Text] [PDF]
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 U. Theissen, M. Hoffmeister, M. Grieshaber, and W. Martin Single Eubacterial Origin of Eukaryotic Sulfide:Quinone Oxidoreductase, a Mitochondrial Enzyme Conserved from the Early Evolution of Eukaryotes During Anoxic and Sulfidic Times Mol. Biol. Evol., September 1, 2003; 20(9): 1564 - 1574. [Abstract] [Full Text] [PDF]
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R. Dutkiewicz, B. Schilke, H. Knieszner, W. Walter, E. A. Craig, and J. Marszalek Ssq1, a Mitochondrial Hsp70 Involved in Iron-Sulfur (Fe/S) Center Biogenesis: SIMILARITIES TO AND DIFFERENCES FROM ITS BACTERIAL COUNTERPART J. Biol. Chem., August 8, 2003; 278(32): 29719 - 29727. [Abstract] [Full Text] [PDF]
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G. Tan, E. Napoli, F. Taroni, and G. Cortopassi Decreased expression of genes involved in sulfur amino acid metabolism in frataxin-deficient cells Hum. Mol. Genet., July 15, 2003; 12(14): 1699 - 1711. [Abstract] [Full Text] [PDF]
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G. Duby, F. Foury, A. Ramazzotti, J. Herrmann, and T. Lutz A non-essential function for yeast frataxin in iron-sulfur cluster assembly Hum. Mol. Genet., October 2, 2002; 11(21): 2635 - 2643. [Abstract] [Full Text] [PDF]
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U. Muhlenhoff, N. Richhardt, M. Ristow, G. Kispal, and R. Lill The yeast frataxin homolog Yfh1p plays a specific role in the maturation of cellular Fe/S proteins Hum. Mol. Genet., August 15, 2002; 11(17): 2025 - 2036. [Abstract] [Full Text] [PDF]
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S. Adinolfi, M. Trifuoggi, A. S. Politou, S. Martin, and A. Pastore A structural approach to understanding the iron-binding properties of phylogenetically different frataxins Hum. Mol. Genet., August 1, 2002; 11(16): 1865 - 1877. [Abstract] [Full Text] [PDF]
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F. Foury and T. Roganti Deletion of the Mitochondrial Carrier Genes MRS3 and MRS4 Suppresses Mitochondrial Iron Accumulation in a Yeast Frataxin-deficient Strain J. Biol. Chem., June 28, 2002; 277(27): 24475 - 24483. [Abstract] [Full Text] [PDF]
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S. A. Shoichet, A. T. Baumer, D. Stamenkovic, H. Sauer, A. F. H. Pfeiffer, C. R. Kahn, D. Muller-Wieland, C. Richter, and M. Ristow Frataxin promotes antioxidant defense in a thiol-dependent manner resulting in diminished malignant transformation in vitro Hum. Mol. Genet., April 1, 2002; 11(7): 815 - 821. [Abstract] [Full Text] [PDF]
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P. Cavadini, H. A. O'Neill, O. Benada, and G. Isaya Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia Hum. Mol. Genet., February 1, 2002; 11(3): 217 - 227. [Abstract] [Full Text] [PDF]
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