| Structural highlights
Disease
[FRDA_HUMAN] Defects in FXN are the cause of Friedreich ataxia (FRDA) [MIM:229300]. FRDA is an autosomal recessive, progressive degenerative disease characterized by neurodegeneration and cardiomyopathy it is the most common inherited ataxia. The disorder is usually manifest before adolescence and is generally characterized by incoordination of limb movements, dysarthria, nystagmus, diminished or absent tendon reflexes, Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus, and hammer toe. In most patients, FRDA is due to GAA triplet repeat expansions in the first intron of the frataxin gene. But in some cases the disease is due to mutations in the coding region.[:][:][1] [2] [3] [4] [:][5] [6]
Function
[FRDA_HUMAN] Promotes the biosynthesis of heme and assembly and repair of iron-sulfur clusters by delivering Fe(2+) to proteins involved in these pathways. May play a role in the protection against iron-catalyzed oxidative stress through its ability to catalyze the oxidation of Fe(2+) to Fe(3+); the oligomeric form but not the monomeric form has in vitro ferroxidase activity. May be able to store large amounts of iron in the form of a ferrihydrite mineral by oligomerization; however, the physiological relevance is unsure as reports are conflicting and the function has only been shown using heterologous overexpression systems. Modulates the RNA-binding activity of ACO1.[7] [8] [9] [10] [11] [12] [13] [14] [15]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Friedreich's ataxia, an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia, cardiomyopathy, and diabetes mellitus, is caused by decreased frataxin production or function. The structure of human frataxin, which we have determined at 1.8-A resolution, reveals a novel protein fold. A five-stranded, antiparallel beta sheet provides a flat platform, which supports a pair of parallel alpha helices, to form a compact alphabeta sandwich. A cluster of 12 acidic residues from the first 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-A(2) patch on a distinct surface of the protein. Side chains of disease-associated mutations either contribute to the anionic patch, help create the second conserved surface, or point toward frataxin's hydrophobic core. These structural findings predict potential modes of protein-protein and protein-iron binding.
Crystal structure of human frataxin.,Dhe-Paganon S, Shigeta R, Chi YI, Ristow M, Shoelson SE J Biol Chem. 2000 Oct 6;275(40):30753-6. PMID:10900192[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Bidichandani SI, Ashizawa T, Patel PI. Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion. Am J Hum Genet. 1997 May;60(5):1251-6. PMID:9150176
- ↑ Bartolo C, Mendell JR, Prior TW. Identification of a missense mutation in a Friedreich's ataxia patient: implications for diagnosis and carrier studies. Am J Med Genet. 1998 Oct 12;79(5):396-9. PMID:9779809
- ↑ Forrest SM, Knight M, Delatycki MB, Paris D, Williamson R, King J, Yeung L, Nassif N, Nicholson GA. The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene. Neurogenetics. 1998 Aug;1(4):253-7. PMID:10732799
- ↑ Cossee M, Durr A, Schmitt M, Dahl N, Trouillas P, Allinson P, Kostrzewa M, Nivelon-Chevallier A, Gustavson KH, Kohlschutter A, Muller U, Mandel JL, Brice A, Koenig M, Cavalcanti F, Tammaro A, De Michele G, Filla A, Cocozza S, Labuda M, Montermini L, Poirier J, Pandolfo M. Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes. Ann Neurol. 1999 Feb;45(2):200-6. PMID:9989622
- ↑ Al-Mahdawi S, Pook M, Chamberlain S. A novel missense mutation (L198R) in the Friedreich's ataxia gene. Hum Mutat. 2000 Jul;16(1):95. PMID:10874325 doi:<95::AID-HUMU29>3.0.CO;2-E 10.1002/1098-1004(200007)16:1<95::AID-HUMU29>3.0.CO;2-E
- ↑ Calmels N, Schmucker S, Wattenhofer-Donze M, Martelli A, Vaucamps N, Reutenauer L, Messaddeq N, Bouton C, Koenig M, Puccio H. The first cellular models based on frataxin missense mutations that reproduce spontaneously the defects associated with Friedreich ataxia. PLoS One. 2009 Jul 24;4(7):e6379. PMID:19629184 doi:10.1371/journal.pone.0006379
- ↑ Condo I, Malisan F, Guccini I, Serio D, Rufini A, Testi R. Molecular control of the cytosolic aconitase/IRP1 switch by extramitochondrial frataxin. Hum Mol Genet. 2010 Jan 20. PMID:20053667 doi:ddp592
- ↑ Cavadini P, O'Neill HA, Benada O, Isaya G. Assembly and iron-binding properties of human frataxin, the protein deficient in Friedreich ataxia. Hum Mol Genet. 2002 Feb 1;11(3):217-27. PMID:11823441
- ↑ Nichol H, Gakh O, O'Neill HA, Pickering IJ, Isaya G, George GN. Structure of frataxin iron cores: an X-ray absorption spectroscopic study. Biochemistry. 2003 May 27;42(20):5971-6. PMID:12755598 doi:10.1021/bi027021l
- ↑ Yoon T, Cowan JA. Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins. J Am Chem Soc. 2003 May 21;125(20):6078-84. PMID:12785837 doi:10.1021/ja027967i
- ↑ Yoon T, Cowan JA. Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. J Biol Chem. 2004 Jun 18;279(25):25943-6. Epub 2004 Apr 27. PMID:15123683 doi:10.1074/jbc.C400107200
- ↑ Bulteau AL, O'Neill HA, Kennedy MC, Ikeda-Saito M, Isaya G, Szweda LI. Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science. 2004 Jul 9;305(5681):242-5. PMID:15247478 doi:10.1126/science.1098991
- ↑ O'Neill HA, Gakh O, Park S, Cui J, Mooney SM, Sampson M, Ferreira GC, Isaya G. Assembly of human frataxin is a mechanism for detoxifying redox-active iron. Biochemistry. 2005 Jan 18;44(2):537-45. PMID:15641778 doi:10.1021/bi048459j
- ↑ Schoenfeld RA, Napoli E, Wong A, Zhan S, Reutenauer L, Morin D, Buckpitt AR, Taroni F, Lonnerdal B, Ristow M, Puccio H, Cortopassi GA. Frataxin deficiency alters heme pathway transcripts and decreases mitochondrial heme metabolites in mammalian cells. Hum Mol Genet. 2005 Dec 15;14(24):3787-99. Epub 2005 Oct 20. PMID:16239244 doi:10.1093/hmg/ddi393
- ↑ Condo I, Ventura N, Malisan F, Tomassini B, Testi R. A pool of extramitochondrial frataxin that promotes cell survival. J Biol Chem. 2006 Jun 16;281(24):16750-6. Epub 2006 Apr 11. PMID:16608849 doi:M511960200
- ↑ Dhe-Paganon S, Shigeta R, Chi YI, Ristow M, Shoelson SE. Crystal structure of human frataxin. J Biol Chem. 2000 Oct 6;275(40):30753-6. PMID:10900192 doi:10.1074/jbc.C000407200
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