Frataxin, mitochondrial

Details

Name
Frataxin, mitochondrial
Synonyms
  • 1.16.3.1
  • FRDA
  • Friedreich ataxia protein
  • Fxn
  • X25
Gene Name
FXN
Organism
Humans
Amino acid sequence
>lcl|BSEQ0049696|Frataxin, mitochondrial
MWTLGRRAVAGLLASPSPAQAQTLTRVPRPAELAPLCGRRGLRTDIDATCTPRRASSNQR
GLNQIWNVKKQSVYLMNLRKSGTLGHPGSLDETTYERLAEETLDSLAEFFEDLADKPYTF
EDYDVSFGSGVLTVKLGGDLGTYVINKQTPNKQIWLSSPSSGPKRYDWTGKNWVYSHDGV
SLHELLAAELTKALKTKLDLSSLAYSGKDA
Number of residues
210
Molecular Weight
23134.895
Theoretical pI
Not Available
GO Classification
Functions
2 iron, 2 sulfur cluster binding / ferric iron binding / ferrous iron binding / ferroxidase activity / iron chaperone activity / iron-sulfur cluster binding
Processes
adult walking behavior / aerobic respiration / cellular iron ion homeostasis / cellular response to hydrogen peroxide / embryo development ending in birth or egg hatching / heme biosynthetic process / ion transport / iron incorporation into metallo-sulfur cluster / mitochondrion organization / negative regulation of apoptotic process / negative regulation of multicellular organism growth / negative regulation of organ growth / negative regulation of release of cytochrome c from mitochondria / oxidative phosphorylation / positive regulation of aconitate hydratase activity / positive regulation of catalytic activity / positive regulation of cell growth / positive regulation of cell proliferation / positive regulation of lyase activity / positive regulation of succinate dehydrogenase activity / proprioception / protein autoprocessing / regulation of ferrochelatase activity / response to iron ion / small molecule metabolic process
Components
cytosol / mitochondrial matrix / mitochondrion
General Function
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.
Specific Function
2 iron, 2 sulfur cluster binding
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Mitochondrion
Gene sequence
>lcl|BSEQ0049697|Frataxin, mitochondrial (FXN)
ATGTGGACTCTCGGGCGCCGCGCAGTAGCCGGCCTCCTGGCGTCACCCAGCCCAGCCCAG
GCCCAGACCCTCACCCGGGTCCCGCGGCCGGCAGAGTTGGCCCCACTCTGCGGCCGCCGT
GGCCTGCGCACCGACATCGATGCGACCTGCACGCCCCGCCGCGCAAGTTCGAACCAACGT
GGCCTCAACCAGATTTGGAATGTCAAAAAGCAGAGTGTCTATTTGATGAATTTGAGGAAA
TCTGGAACTTTGGGCCACCCAGGCTCTCTAGATGAGACCACCTATGAAAGACTAGCAGAG
GAAACGCTGGACTCTTTAGCAGAGTTTTTTGAAGACCTTGCAGACAAGCCATACACGTTT
GAGGACTATGATGTCTCCTTTGGGAGTGGTGTCTTAACTGTCAAACTGGGTGGAGATCTA
GGAACCTATGTGATCAACAAGCAGACGCCAAACAAGCAAATCTGGCTATCTTCTCCATCC
AGTGGACCTAAGCGTTATGACTGGACTGGGAAAAACTGGGTGTACTCCCACGACGGCGTG
TCCCTCCATGAGCTGCTGGCCGCAGAGCTCACTAAAGCCTTAAAAACCAAACTGGACTTG
TCTTCCTTGGCCTATTCCGGAAAAGATGCTTGA
Chromosome Location
9
Locus
9q21.11
External Identifiers
ResourceLink
UniProtKB IDQ16595
UniProtKB Entry NameFRDA_HUMAN
HGNC IDHGNC:3951
General References
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  4. Schmucker S, Argentini M, Carelle-Calmels N, Martelli A, Puccio H: The in vivo mitochondrial two-step maturation of human frataxin. Hum Mol Genet. 2008 Nov 15;17(22):3521-31. doi: 10.1093/hmg/ddn244. Epub 2008 Aug 25. [PubMed:18725397]
  5. Condo I, Ventura N, Malisan F, Rufini A, Tomassini B, Testi R: In vivo maturation of human frataxin. Hum Mol Genet. 2007 Jul 1;16(13):1534-40. Epub 2007 Apr 27. [PubMed:17468497]
  6. 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 Apr 1;19(7):1221-9. doi: 10.1093/hmg/ddp592. Epub 2010 Jan 6. [PubMed:20053667]
  7. Campuzano V, Montermini L, Lutz Y, Cova L, Hindelang C, Jiralerspong S, Trottier Y, Kish SJ, Faucheux B, Trouillas P, Authier FJ, Durr A, Mandel JL, Vescovi A, Pandolfo M, Koenig M: Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum Mol Genet. 1997 Oct;6(11):1771-80. [PubMed:9302253]
  8. Koutnikova H, Campuzano V, Foury F, Dolle P, Cazzalini O, Koenig M: Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nat Genet. 1997 Aug;16(4):345-51. [PubMed:9241270]
  9. Gordon DM, Shi Q, Dancis A, Pain D: Maturation of frataxin within mammalian and yeast mitochondria: one-step processing by matrix processing peptidase. Hum Mol Genet. 1999 Nov;8(12):2255-62. [PubMed:10545606]
  10. Branda SS, Cavadini P, Adamec J, Kalousek F, Taroni F, Isaya G: Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase. J Biol Chem. 1999 Aug 6;274(32):22763-9. [PubMed:10428860]
  11. Cavadini P, Adamec J, Taroni F, Gakh O, Isaya G: Two-step processing of human frataxin by mitochondrial processing peptidase. Precursor and intermediate forms are cleaved at different rates. J Biol Chem. 2000 Dec 29;275(52):41469-75. [PubMed:11020385]
  12. 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. [PubMed:11823441]
  13. 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. [PubMed:12755598]
  14. 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. [PubMed:12785837]
  15. 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. [PubMed:15123683]
  16. 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. [PubMed:15247478]
  17. 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. [PubMed:15641778]
  18. Gonzalez-Cabo P, Vazquez-Manrique RP, Garcia-Gimeno MA, Sanz P, Palau F: Frataxin interacts functionally with mitochondrial electron transport chain proteins. Hum Mol Genet. 2005 Aug 1;14(15):2091-8. Epub 2005 Jun 16. [PubMed:15961414]
  19. 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. [PubMed:16239244]
  20. Acquaviva F, De Biase I, Nezi L, Ruggiero G, Tatangelo F, Pisano C, Monticelli A, Garbi C, Acquaviva AM, Cocozza S: 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. 2005 Sep 1;118(Pt 17):3917-24. Epub 2005 Aug 9. [PubMed:16091420]
  21. O'Neill HA, Gakh O, Isaya G: Supramolecular assemblies of human frataxin are formed via subunit-subunit interactions mediated by a non-conserved amino-terminal region. J Mol Biol. 2005 Jan 21;345(3):433-9. [PubMed:15581888]
  22. 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. [PubMed:16608849]
  23. Shan Y, Napoli E, Cortopassi G: Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones. Hum Mol Genet. 2007 Apr 15;16(8):929-41. Epub 2007 Mar 1. [PubMed:17331979]
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  26. 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. [PubMed:10900192]
  27. Musco G, Stier G, Kolmerer B, Adinolfi S, Martin S, Frenkiel T, Gibson T, Pastore A: Towards a structural understanding of Friedreich's ataxia: the solution structure of frataxin. Structure. 2000 Jul 15;8(7):695-707. [PubMed:10903947]
  28. 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. [PubMed:9150176]
  29. 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. [PubMed:9779809]
  30. 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. [PubMed:10732799]
  31. 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. [PubMed:9989622]
  32. 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. [PubMed:10874325]
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Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB01592IronapprovedunknownDetails
DB14488Ferrous gluconateapprovedunknownDetails
DB14489Ferrous succinateapprovedunknownDetails
DB14490Ferrous ascorbateapprovedunknownDetails
DB14491Ferrous fumarateapprovedunknownDetails
DB14501Ferrous glycine sulfateapprovedunknownDetails