FRDA_HUMAN
ID FRDA_HUMAN Reviewed; 210 AA.
AC Q16595; A8MXJ6; C9JJ89; O15545; O95656; Q15294; Q5VZ01;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 15-JUL-1999, sequence version 2.
DT 03-AUG-2022, entry version 216.
DE RecName: Full=Frataxin, mitochondrial;
DE EC=1.16.3.1;
DE AltName: Full=Friedreich ataxia protein;
DE Short=Fxn;
DE Contains:
DE RecName: Full=Frataxin intermediate form;
DE Short=i-FXN;
DE Contains:
DE RecName: Full=Frataxin(56-210);
DE AltName: Full=m56-FXN;
DE Contains:
DE RecName: Full=Frataxin(78-210);
DE AltName: Full=d-FXN;
DE AltName: Full=m78-FXN;
DE Contains:
DE RecName: Full=Frataxin mature form;
DE AltName: Full=Frataxin(81-210);
DE AltName: Full=m81-FXN;
DE Flags: Precursor;
GN Name=FXN; Synonyms=FRDA, X25;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), ALTERNATIVE
RP SPLICING, AND VARIANT PHE-154.
RX PubMed=8596916; DOI=10.1126/science.271.5254.1423;
RA Campuzano V., Montermini L., Molto M.D., Pianese L., Cossee M.,
RA Cavalcanti F., Monros E., Rodius F., Duclos F., Monticelli A., Zara F.,
RA Canizares J., Koutnikova H., Bidichandani S., Gellera C., Brice A.,
RA Trouillas P., de Michele G., Filla A., de Frutos R., Palau F., Patel P.I.,
RA di Donato S., Mandel J.-L., Cocozza S., Koenig M., Pandolfo M.;
RT "Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA
RT triplet repeat expansion.";
RL Science 271:1423-1427(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP PROTEIN SEQUENCE OF 81-90, PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION,
RP AND MUTAGENESIS OF 39-ARG-ARG-40; 53-ARG-ARG-54; 78-LEU-ARG-79 AND
RP 79-ARG-LYS-80.
RX PubMed=18725397; DOI=10.1093/hmg/ddn244;
RA Schmucker S., Argentini M., Carelle-Calmels N., Martelli A., Puccio H.;
RT "The in vivo mitochondrial two-step maturation of human frataxin.";
RL Hum. Mol. Genet. 17:3521-3531(2008).
RN [5]
RP PROTEIN SEQUENCE OF 81-86, PROTEOLYTIC PROCESSING, MUTAGENESIS OF
RP 53-ARG-ARG-54 AND 79-ARG-LYS-80, AND TISSUE SPECIFICITY.
RX PubMed=17468497; DOI=10.1093/hmg/ddm102;
RA Condo I., Ventura N., Malisan F., Rufini A., Tomassini B., Testi R.;
RT "In vivo maturation of human frataxin.";
RL Hum. Mol. Genet. 16:1534-1540(2007).
RN [6]
RP PROTEIN SEQUENCE OF 81-86, FUNCTION, INTERACTION WITH ACO1, AND SUBCELLULAR
RP LOCATION.
RX PubMed=20053667; DOI=10.1093/hmg/ddp592;
RA Condo I., Malisan F., Guccini I., Serio D., Rufini A., Testi R.;
RT "Molecular control of the cytosolic aconitase/IRP1 switch by
RT extramitochondrial frataxin.";
RL Hum. Mol. Genet. 19:1221-1229(2010).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 89-128, AND VARIANT FRDA TYR-122.
RA Kostrzewa M.;
RL Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 89-128, AND VARIANT FRDA TYR-122.
RA Doudney J.D., Pook M.A., Al-Mahdawi S., Carvajal J.J., Hillerman R.,
RA Chamberlain S.;
RT "A novel splice site mutation (384+1G-A) in the Friedreich's ataxia gene.";
RL Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 162-210.
RA Laccone F., Schloesser M.;
RT "Correct sequence in exon 5a of x25: human frataxin (FRDA),
RT F175(TTC)-->Y175(TAC) and W202(TGG)-->S202(TCC).";
RL Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP SUBCELLULAR LOCATION.
RX PubMed=9302253; DOI=10.1093/hmg/6.11.1771;
RA Campuzano V., Montermini L., Lutz Y., Cova L., Hindelang C.,
RA Jiralerspong S., Trottier Y., Kish S.J., Faucheux B., Trouillas P.,
RA Authier F.J., Duerr A., Mandel J.-L., Vescovi A., Pandolfo M., Koenig M.;
RT "Frataxin is reduced in Friedreich ataxia patients and is associated with
RT mitochondrial membranes.";
RL Hum. Mol. Genet. 6:1771-1780(1997).
RN [11]
RP SUBCELLULAR LOCATION.
RX PubMed=9241270; DOI=10.1038/ng0897-345;
RA Koutnikova H., Campuzano V., Foury F., Dolle P., Cazzalini O., Koenig M.;
RT "Studies of human, mouse and yeast homologues indicate a mitochondrial
RT function for frataxin.";
RL Nat. Genet. 16:345-351(1997).
RN [12]
RP PROTEOLYTIC PROCESSING.
RX PubMed=10545606; DOI=10.1093/hmg/8.12.2255;
RA Gordon D.M., Shi Q., Dancis A., Pain D.;
RT "Maturation of frataxin within mammalian and yeast mitochondria: one-step
RT processing by matrix processing peptidase.";
RL Hum. Mol. Genet. 8:2255-2262(1999).
RN [13]
RP PROTEOLYTIC PROCESSING.
RX PubMed=10428860; DOI=10.1074/jbc.274.32.22763;
RA Branda S.S., Cavadini P., Adamec J., Kalousek F., Taroni F., Isaya G.;
RT "Yeast and human frataxin are processed to mature form in two sequential
RT steps by the mitochondrial processing peptidase.";
RL J. Biol. Chem. 274:22763-22769(1999).
RN [14]
RP PROTEOLYTIC PROCESSING.
RX PubMed=11020385; DOI=10.1074/jbc.m006539200;
RA Cavadini P., Adamec J., Taroni F., Gakh O., Isaya G.;
RT "Two-step processing of human frataxin by mitochondrial processing
RT peptidase. Precursor and intermediate forms are cleaved at different
RT rates.";
RL J. Biol. Chem. 275:41469-41475(2000).
RN [15]
RP POSSIBLE FUNCTION IN IRON STORAGE, AND SUBUNIT.
RX PubMed=11823441; DOI=10.1093/hmg/11.3.217;
RA Cavadini P., O'Neill H.A., Benada O., Isaya G.;
RT "Assembly and iron-binding properties of human frataxin, the protein
RT deficient in Friedreich ataxia.";
RL Hum. Mol. Genet. 11:217-227(2002).
RN [16]
RP POSSIBLE FUNCTION IN IRON STORAGE, AND SUBUNIT.
RX PubMed=12755598; DOI=10.1021/bi027021l;
RA Nichol H., Gakh O., O'Neill H.A., Pickering I.J., Isaya G., George G.N.;
RT "Structure of frataxin iron cores: an X-ray absorption spectroscopic
RT study.";
RL Biochemistry 42:5971-5976(2003).
RN [17]
RP FUNCTION IN IRON-SULFUR CLUSTER BIOSYNTHESIS, AND INTERACTION WITH ISCU.
RX PubMed=12785837; DOI=10.1021/ja027967i;
RA Yoon T., Cowan J.A.;
RT "Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron
RT donor for assembly of [2Fe-2S] clusters in ISU-type proteins.";
RL J. Am. Chem. Soc. 125:6078-6084(2003).
RN [18]
RP POSSIBLE FUNCTION IN HEME BIOSYNTHESIS, AND INTERACTION WITH FECH.
RX PubMed=15123683; DOI=10.1074/jbc.c400107200;
RA Yoon T., Cowan J.A.;
RT "Frataxin-mediated iron delivery to ferrochelatase in the final step of
RT heme biosynthesis.";
RL J. Biol. Chem. 279:25943-25946(2004).
RN [19]
RP FUNCTION.
RX PubMed=15247478; DOI=10.1126/science.1098991;
RA Bulteau A.L., O'Neill H.A., Kennedy M.C., Ikeda-Saito M., Isaya G.,
RA Szweda L.I.;
RT "Frataxin acts as an iron chaperone protein to modulate mitochondrial
RT aconitase activity.";
RL Science 305:242-245(2004).
RN [20]
RP FUNCTION IN OXIDATIVE STRESS, SUBUNIT, AND CATALYTIC ACTIVITY.
RX PubMed=15641778; DOI=10.1021/bi048459j;
RA O'Neill H.A., Gakh O., Park S., Cui J., Mooney S.M., Sampson M.,
RA Ferreira G.C., Isaya G.;
RT "Assembly of human frataxin is a mechanism for detoxifying redox-active
RT iron.";
RL Biochemistry 44:537-545(2005).
RN [21]
RP INTERACTION WITH SDHA AND SDHB.
RX PubMed=15961414; DOI=10.1093/hmg/ddi214;
RA Gonzalez-Cabo P., Vazquez-Manrique R.P., Garcia-Gimeno M.A., Sanz P.,
RA Palau F.;
RT "Frataxin interacts functionally with mitochondrial electron transport
RT chain proteins.";
RL Hum. Mol. Genet. 14:2091-2098(2005).
RN [22]
RP FUNCTION, AND INVOLVEMENT IN HEME BIOSYNTHESIS.
RX PubMed=16239244; DOI=10.1093/hmg/ddi393;
RA Schoenfeld R.A., Napoli E., Wong A., Zhan S., Reutenauer L., Morin D.,
RA Buckpitt A.R., Taroni F., Lonnerdal B., Ristow M., Puccio H.,
RA Cortopassi G.A.;
RT "Frataxin deficiency alters heme pathway transcripts and decreases
RT mitochondrial heme metabolites in mammalian cells.";
RL Hum. Mol. Genet. 14:3787-3799(2005).
RN [23]
RP INTERACTION WITH ISCU, AND SUBCELLULAR LOCATION.
RX PubMed=16091420; DOI=10.1242/jcs.02516;
RA Acquaviva F., De Biase I., Nezi L., Ruggiero G., Tatangelo F., Pisano C.,
RA Monticelli A., Garbi C., Acquaviva A.M., Cocozza S.;
RT "Extra-mitochondrial localisation of frataxin and its association with
RT IscU1 during enterocyte-like differentiation of the human colon
RT adenocarcinoma cell line Caco-2.";
RL J. Cell Sci. 118:3917-3924(2005).
RN [24]
RP SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=15581888; DOI=10.1016/j.jmb.2004.10.074;
RA O'Neill H.A., Gakh O., Isaya G.;
RT "Supramolecular assemblies of human frataxin are formed via subunit-subunit
RT interactions mediated by a non-conserved amino-terminal region.";
RL J. Mol. Biol. 345:433-439(2005).
RN [25]
RP FUNCTION IN CELL SURVIVAL, AND SUBCELLULAR LOCATION.
RX PubMed=16608849; DOI=10.1074/jbc.m511960200;
RA Condo I., Ventura N., Malisan F., Tomassini B., Testi R.;
RT "A pool of extramitochondrial frataxin that promotes cell survival.";
RL J. Biol. Chem. 281:16750-16756(2006).
RN [26]
RP INTERACTION WITH LYRM4 AND HSPA9, AND CHARACTERIZATION OF VARIANTS PHE-154
RP AND ARG-155.
RX PubMed=17331979; DOI=10.1093/hmg/ddm038;
RA Shan Y., Napoli E., Cortopassi G.;
RT "Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and
RT multiple mitochondrial chaperones.";
RL Hum. Mol. Genet. 16:929-941(2007).
RN [27]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [28]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [29]
RP INTERACTION WITH HSPA9.
RX PubMed=26702583; DOI=10.1016/j.mito.2015.12.005;
RA Shan Y., Cortopassi G.;
RT "Mitochondrial Hspa9/Mortalin regulates erythroid differentiation via iron-
RT sulfur cluster assembly.";
RL Mitochondrion 26:94-103(2016).
RN [30]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 88-210.
RX PubMed=10900192; DOI=10.1074/jbc.c000407200;
RA Dhe-Paganon S., Shigeta R., Chi Y.-I., Ristow M., Shoelson S.E.;
RT "Crystal structure of human frataxin.";
RL J. Biol. Chem. 275:30753-30756(2000).
RN [31]
RP STRUCTURE BY NMR OF 91-210.
RX PubMed=10903947; DOI=10.1016/s0969-2126(00)00158-1;
RA Musco G., Stier G., Kolmerer B., Adinolfi S., Martin S., Frenkiel T.,
RA Gibson T., Pastore A.;
RT "Towards a structural understanding of Friedreich's ataxia: the solution
RT structure of frataxin.";
RL Structure 8:695-707(2000).
RN [32]
RP VARIANTS FRDA VAL-130 AND PHE-154.
RX PubMed=9150176;
RA Bidichandani S.I., Ashizawa T., Patel P.I.;
RT "Atypical Friedreich ataxia caused by compound heterozygosity for a novel
RT missense mutation and the GAA triplet-repeat expansion.";
RL Am. J. Hum. Genet. 60:1251-1256(1997).
RN [33]
RP VARIANT FRDA SER-106.
RX PubMed=9779809;
RX DOI=10.1002/(sici)1096-8628(19981012)79:5<396::aid-ajmg13>3.0.co;2-m;
RA Bartolo C., Mendell J.R., Prior T.W.;
RT "Identification of a missense mutation in a Friedreich's ataxia patient:
RT implications for diagnosis and carrier studies.";
RL Am. J. Med. Genet. 79:396-399(1998).
RN [34]
RP VARIANTS FRDA VAL-130; CYS-165 AND PHE-182.
RX PubMed=10732799; DOI=10.1007/s100480050037;
RA Forrest S.M., Knight M., Delatycki M.B., Paris D., Williamson R., King J.,
RA Yeung L., Nassif N., Nicholson G.A.;
RT "The correlation of clinical phenotype in Friedreich ataxia with the site
RT of point mutations in the FRDA gene.";
RL Neurogenetics 1:253-257(1998).
RN [35]
RP VARIANTS FRDA TYR-122 AND VAL-130.
RX PubMed=9989622;
RX DOI=10.1002/1531-8249(199902)45:2<200::aid-ana10>3.0.co;2-u;
RA Cossee M., Duerr A., Schmitt M., Dahl N., Trouillas P., Allinson P.,
RA Kostrzewa M., Nivelon-Chevallier A., Gustavson K.-H., Kohlschuetter A.,
RA Mueller U., Mandel J.-L., Brice A., Koenig M., Cavalcanti F., Tammaro A.,
RA de Michele G., Filla A., Cocozza S., Labuda M., Montermini L., Poirier J.,
RA Pandolfo M.;
RT "Friedreich's ataxia: point mutations and clinical presentation of compound
RT heterozygotes.";
RL Ann. Neurol. 45:200-206(1999).
RN [36]
RP VARIANT FRDA ARG-155.
RA Labuda M., Poirier J., Pandolfo M.;
RT "A missense mutation (W155R) in an American patient with Friedreich's
RT ataxia.";
RL Hum. Mutat. 13:506-506(1999).
RN [37]
RP VARIANT FRDA ARG-198.
RX PubMed=10874325;
RX DOI=10.1002/1098-1004(200007)16:1<95::aid-humu29>3.0.co;2-e;
RA Al-Mahdawi S., Pook M., Chamberlain S.;
RT "A novel missense mutation (L198R) in the Friedreich's ataxia gene.";
RL Hum. Mutat. 16:95-95(2000).
RN [38]
RP CHARACTERIZATION OF VARIANT FRDA PHE-154.
RX PubMed=19629184; DOI=10.1371/journal.pone.0006379;
RA Calmels N., Schmucker S., Wattenhofer-Donze M., Martelli A., Vaucamps N.,
RA Reutenauer L., Messaddeq N., Bouton C., Koenig M., Puccio H.;
RT "The first cellular models based on frataxin missense mutations that
RT reproduce spontaneously the defects associated with Friedreich ataxia.";
RL PLoS ONE 4:E6379-E6379(2009).
CC -!- FUNCTION: Promotes the biosynthesis of heme and assembly and repair of
CC iron-sulfur clusters by delivering Fe(2+) to proteins involved in these
CC pathways. May play a role in the protection against iron-catalyzed
CC oxidative stress through its ability to catalyze the oxidation of
CC Fe(2+) to Fe(3+); the oligomeric form but not the monomeric form has in
CC vitro ferroxidase activity. May be able to store large amounts of iron
CC in the form of a ferrihydrite mineral by oligomerization; however, the
CC physiological relevance is unsure as reports are conflicting and the
CC function has only been shown using heterologous overexpression systems.
CC Modulates the RNA-binding activity of ACO1.
CC {ECO:0000269|PubMed:12785837, ECO:0000269|PubMed:15247478,
CC ECO:0000269|PubMed:15641778, ECO:0000269|PubMed:16239244,
CC ECO:0000269|PubMed:16608849, ECO:0000269|PubMed:20053667}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4 Fe(2+) + 4 H(+) + O2 = 4 Fe(3+) + 2 H2O;
CC Xref=Rhea:RHEA:11148, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:29033, ChEBI:CHEBI:29034; EC=1.16.3.1;
CC Evidence={ECO:0000269|PubMed:15641778};
CC -!- SUBUNIT: Monomer (probable predominant form). Oligomer. Monomers and
CC polymeric aggregates of >1 MDa have been isolated from mitochondria. A
CC small fraction of heterologous overexpressed recombinant frataxin forms
CC high-molecular weight aggregates that incorporate iron
CC (PubMed:11823441, PubMed:12755598, PubMed:15641778, PubMed:15581888).
CC Interacts with LYRM4 (PubMed:17331979). Interacts with ACO1
CC (PubMed:20053667). Interacts with ISCU isoform 1 and isoform 2
CC (PubMed:12785837, PubMed:16091420). Interacts with FECH; one iron-bound
CC FXN monomer seems to interact with a FECH homodimer (PubMed:15123683).
CC Interacts with SDHA and SDHB (PubMed:15961414). Interacts with ACO2;
CC the interaction is dependent on citrate (By similarity). Interacts with
CC HSPA9 (PubMed:17331979, PubMed:26702583).
CC {ECO:0000250|UniProtKB:D3ZYW7, ECO:0000269|PubMed:11823441,
CC ECO:0000269|PubMed:12755598, ECO:0000269|PubMed:12785837,
CC ECO:0000269|PubMed:15123683, ECO:0000269|PubMed:15581888,
CC ECO:0000269|PubMed:15641778, ECO:0000269|PubMed:15961414,
CC ECO:0000269|PubMed:16091420, ECO:0000269|PubMed:17331979,
CC ECO:0000269|PubMed:20053667, ECO:0000269|PubMed:26702583}.
CC -!- INTERACTION:
CC Q16595; Q9BVU5: ARL17; NbExp=3; IntAct=EBI-949340, EBI-25857117;
CC Q16595; Q9HC96: CAPN10; NbExp=3; IntAct=EBI-949340, EBI-3915761;
CC Q16595; Q92828: CORO2A; NbExp=3; IntAct=EBI-949340, EBI-2835660;
CC Q16595; Q9UN19: DAPP1; NbExp=6; IntAct=EBI-949340, EBI-3918199;
CC Q16595; A6NEM1: GOLGA6L9; NbExp=3; IntAct=EBI-949340, EBI-5916454;
CC Q16595; O75925: PIAS1; NbExp=3; IntAct=EBI-949340, EBI-629434;
CC Q16595; Q9NS23-4: RASSF1; NbExp=3; IntAct=EBI-949340, EBI-438710;
CC Q16595; Q8WVD3: RNF138; NbExp=3; IntAct=EBI-949340, EBI-749039;
CC Q16595; Q96D59: RNF183; NbExp=3; IntAct=EBI-949340, EBI-743938;
CC Q16595; Q8N6K7-2: SAMD3; NbExp=3; IntAct=EBI-949340, EBI-11528848;
CC Q16595; Q9GZS3: WDR61; NbExp=3; IntAct=EBI-949340, EBI-358545;
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:15581888,
CC ECO:0000269|PubMed:16091420, ECO:0000269|PubMed:16608849,
CC ECO:0000269|PubMed:18725397, ECO:0000269|PubMed:20053667,
CC ECO:0000269|PubMed:9241270, ECO:0000269|PubMed:9302253}. Cytoplasm,
CC cytosol {ECO:0000269|PubMed:16091420, ECO:0000269|PubMed:16608849,
CC ECO:0000269|PubMed:20053667}. Note=PubMed:18725397 reports localization
CC exclusively in mitochondria. {ECO:0000305|PubMed:18725397}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q16595-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q16595-2; Sequence=VSP_001576;
CC Name=3;
CC IsoId=Q16595-3; Sequence=VSP_047282;
CC -!- TISSUE SPECIFICITY: Expressed in the heart, peripheral blood
CC lymphocytes and dermal fibroblasts. {ECO:0000269|PubMed:17468497}.
CC -!- PTM: Processed in two steps by mitochondrial processing peptidase
CC (MPP). MPP first cleaves the precursor to intermediate form and
CC subsequently converts the intermediate to yield frataxin mature form
CC (frataxin(81-210)) which is the predominant form. The additional forms,
CC frataxin(56-210) and frataxin(78-210), seem to be produced when the
CC normal maturation process is impaired; their physiological relevance is
CC unsure. {ECO:0000269|PubMed:10428860, ECO:0000269|PubMed:10545606,
CC ECO:0000269|PubMed:11020385, ECO:0000269|PubMed:17468497,
CC ECO:0000269|PubMed:18725397}.
CC -!- DISEASE: Friedreich ataxia (FRDA) [MIM:229300]: Autosomal recessive,
CC progressive degenerative disease characterized by neurodegeneration and
CC cardiomyopathy it is the most common inherited ataxia. The disorder is
CC usually manifest before adolescence and is generally characterized by
CC incoordination of limb movements, dysarthria, nystagmus, diminished or
CC absent tendon reflexes, Babinski sign, impairment of position and
CC vibratory senses, scoliosis, pes cavus, and hammer toe. In most
CC patients, FRDA is due to GAA triplet repeat expansions in the first
CC intron of the frataxin gene. But in some cases the disease is due to
CC mutations in the coding region. {ECO:0000269|PubMed:10732799,
CC ECO:0000269|PubMed:10874325, ECO:0000269|PubMed:19629184,
CC ECO:0000269|PubMed:9150176, ECO:0000269|PubMed:9779809,
CC ECO:0000269|PubMed:9989622, ECO:0000269|Ref.36, ECO:0000269|Ref.7,
CC ECO:0000269|Ref.8}. Note=The disease is caused by variants affecting
CC the gene represented in this entry.
CC -!- MISCELLANEOUS: The unusual migration profile of mature frataxin on SDS-
CC PAGE due to its acidic N-terminus most likely contributed to
CC conflicting reports for the N-terminus of the mature protein. Unlike
CC prokaryotic and yeast frataxin homologs, which self-assemble at high
CC iron concentrations, oligomerization of human frataxin is not induced
CC by iron. The existence of a specialized mitochondrial ferritin in
CC mammalia (FTMT) is suggesting that iron storage would be redundant
CC function, at least in mammalian mitochondria.
CC -!- MISCELLANEOUS: [Isoform 2]: Not highly expressed and may be
CC artifactual. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the frataxin family. {ECO:0000305}.
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DR EMBL; U43747; AAA98510.1; -; mRNA.
DR EMBL; U43752; AAA98508.1; -; Genomic_DNA.
DR EMBL; U43748; AAA98508.1; JOINED; Genomic_DNA.
DR EMBL; U43749; AAA98508.1; JOINED; Genomic_DNA.
DR EMBL; U43750; AAA98508.1; JOINED; Genomic_DNA.
DR EMBL; U43751; AAA98508.1; JOINED; Genomic_DNA.
DR EMBL; U43753; AAA98509.1; -; Genomic_DNA.
DR EMBL; U43748; AAA98509.1; JOINED; Genomic_DNA.
DR EMBL; U43749; AAA98509.1; JOINED; Genomic_DNA.
DR EMBL; U43750; AAA98509.1; JOINED; Genomic_DNA.
DR EMBL; U43751; AAA98509.1; JOINED; Genomic_DNA.
DR EMBL; AL162730; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC023633; AAH23633.1; -; mRNA.
DR EMBL; BC048097; AAH48097.1; -; mRNA.
DR EMBL; Y13751; CAA74077.1; -; Genomic_DNA.
DR EMBL; AF028240; AAB84047.1; -; Genomic_DNA.
DR EMBL; U93173; AAD00734.1; -; Genomic_DNA.
DR CCDS; CCDS43834.1; -. [Q16595-3]
DR CCDS; CCDS6626.1; -. [Q16595-1]
DR RefSeq; NP_000135.2; NM_000144.4. [Q16595-1]
DR RefSeq; NP_001155178.1; NM_001161706.1.
DR RefSeq; NP_852090.1; NM_181425.2. [Q16595-3]
DR PDB; 1EKG; X-ray; 1.80 A; A=86-210.
DR PDB; 1LY7; NMR; -; A=91-210.
DR PDB; 3S4M; X-ray; 1.30 A; A=82-210.
DR PDB; 3S5D; X-ray; 1.50 A; A=82-210.
DR PDB; 3S5E; X-ray; 1.31 A; A=82-210.
DR PDB; 3S5F; X-ray; 1.50 A; A/B=82-210.
DR PDB; 3T3J; X-ray; 1.70 A; A=82-210.
DR PDB; 3T3K; X-ray; 1.24 A; A=82-210.
DR PDB; 3T3L; X-ray; 1.15 A; A=82-210.
DR PDB; 3T3T; X-ray; 1.38 A; A/B/C/D=82-210.
DR PDB; 3T3X; X-ray; 1.57 A; A/B=82-210.
DR PDB; 5KZ5; EM; 14.30 A; A/B/C/D/E/F/G/H/I/J/K/L=42-210.
DR PDB; 6NZU; EM; 3.20 A; I/J=81-210.
DR PDBsum; 1EKG; -.
DR PDBsum; 1LY7; -.
DR PDBsum; 3S4M; -.
DR PDBsum; 3S5D; -.
DR PDBsum; 3S5E; -.
DR PDBsum; 3S5F; -.
DR PDBsum; 3T3J; -.
DR PDBsum; 3T3K; -.
DR PDBsum; 3T3L; -.
DR PDBsum; 3T3T; -.
DR PDBsum; 3T3X; -.
DR PDBsum; 5KZ5; -.
DR PDBsum; 6NZU; -.
DR AlphaFoldDB; Q16595; -.
DR BMRB; Q16595; -.
DR SASBDB; Q16595; -.
DR SMR; Q16595; -.
DR BioGRID; 108677; 53.
DR ComplexPortal; CPX-5641; Mitochondrial NIAUFX iron-sulfur cluster assembly complex.
DR CORUM; Q16595; -.
DR IntAct; Q16595; 23.
DR MINT; Q16595; -.
DR STRING; 9606.ENSP00000366482; -.
DR ChEMBL; CHEMBL2321640; -.
DR DrugBank; DB14490; Ferrous ascorbate.
DR DrugBank; DB14491; Ferrous fumarate.
DR DrugBank; DB14488; Ferrous gluconate.
DR DrugBank; DB14501; Ferrous glycine sulfate.
DR DrugBank; DB14489; Ferrous succinate.
DR DrugBank; DB01592; Iron.
DR TCDB; 9.B.21.1.1; the frataxin (frataxin) family.
DR iPTMnet; Q16595; -.
DR PhosphoSitePlus; Q16595; -.
DR BioMuta; FXN; -.
DR OGP; Q16595; -.
DR EPD; Q16595; -.
DR jPOST; Q16595; -.
DR MassIVE; Q16595; -.
DR MaxQB; Q16595; -.
DR PaxDb; Q16595; -.
DR PeptideAtlas; Q16595; -.
DR PRIDE; Q16595; -.
DR ProteomicsDB; 2327; -.
DR ProteomicsDB; 60939; -. [Q16595-1]
DR ProteomicsDB; 60940; -. [Q16595-2]
DR TopDownProteomics; Q16595-1; -. [Q16595-1]
DR TopDownProteomics; Q16595-2; -. [Q16595-2]
DR ABCD; Q16595; 1 sequenced antibody.
DR Antibodypedia; 26793; 649 antibodies from 35 providers.
DR DNASU; 2395; -.
DR Ensembl; ENST00000396366.6; ENSP00000379652.2; ENSG00000165060.15. [Q16595-3]
DR Ensembl; ENST00000484259.3; ENSP00000419243.2; ENSG00000165060.15. [Q16595-1]
DR GeneID; 2395; -.
DR KEGG; hsa:2395; -.
DR MANE-Select; ENST00000484259.3; ENSP00000419243.2; NM_000144.5; NP_000135.2.
DR UCSC; uc004agz.3; human. [Q16595-1]
DR CTD; 2395; -.
DR DisGeNET; 2395; -.
DR GeneCards; FXN; -.
DR GeneReviews; FXN; -.
DR HGNC; HGNC:3951; FXN.
DR HPA; ENSG00000165060; Low tissue specificity.
DR MalaCards; FXN; -.
DR MIM; 229300; phenotype.
DR MIM; 606829; gene.
DR neXtProt; NX_Q16595; -.
DR OpenTargets; ENSG00000165060; -.
DR Orphanet; 95; Friedreich ataxia.
DR PharmGKB; PA28369; -.
DR VEuPathDB; HostDB:ENSG00000165060; -.
DR eggNOG; KOG3413; Eukaryota.
DR GeneTree; ENSGT00390000005811; -.
DR GeneTree; ENSGT00940000158634; -.
DR HOGENOM; CLU_080880_1_0_1; -.
DR InParanoid; Q16595; -.
DR OMA; YEVEYHS; -.
DR PhylomeDB; Q16595; -.
DR TreeFam; TF318958; -.
DR PathwayCommons; Q16595; -.
DR Reactome; R-HSA-1268020; Mitochondrial protein import.
DR Reactome; R-HSA-1362409; Mitochondrial iron-sulfur cluster biogenesis.
DR SignaLink; Q16595; -.
DR SIGNOR; Q16595; -.
DR BioGRID-ORCS; 2395; 470 hits in 1061 CRISPR screens.
DR ChiTaRS; FXN; human.
DR EvolutionaryTrace; Q16595; -.
DR GeneWiki; Frataxin; -.
DR GenomeRNAi; 2395; -.
DR Pharos; Q16595; Tbio.
DR PRO; PR:Q16595; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; Q16595; protein.
DR Bgee; ENSG00000165060; Expressed in right lobe of liver and 179 other tissues.
DR ExpressionAtlas; Q16595; baseline and differential.
DR Genevisible; Q16595; HS.
DR GO; GO:0005829; C:cytosol; IDA:BHF-UCL.
DR GO; GO:1990229; C:iron-sulfur cluster assembly complex; IC:ComplexPortal.
DR GO; GO:1990221; C:L-cysteine desulfurase complex; IDA:FlyBase.
DR GO; GO:0005759; C:mitochondrial matrix; ISS:BHF-UCL.
DR GO; GO:0005739; C:mitochondrion; IDA:BHF-UCL.
DR GO; GO:0051537; F:2 iron, 2 sulfur cluster binding; IDA:BHF-UCL.
DR GO; GO:0008199; F:ferric iron binding; IDA:BHF-UCL.
DR GO; GO:0008198; F:ferrous iron binding; IDA:BHF-UCL.
DR GO; GO:0004322; F:ferroxidase activity; IDA:UniProtKB.
DR GO; GO:0034986; F:iron chaperone activity; IDA:BHF-UCL.
DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl.
DR GO; GO:0006879; P:cellular iron ion homeostasis; IMP:BHF-UCL.
DR GO; GO:0070301; P:cellular response to hydrogen peroxide; IDA:UniProtKB.
DR GO; GO:0009792; P:embryo development ending in birth or egg hatching; IEA:Ensembl.
DR GO; GO:0006783; P:heme biosynthetic process; NAS:BHF-UCL.
DR GO; GO:0006811; P:ion transport; IEA:UniProtKB-KW.
DR GO; GO:0018283; P:iron incorporation into metallo-sulfur cluster; IDA:BHF-UCL.
DR GO; GO:0016226; P:iron-sulfur cluster assembly; IDA:FlyBase.
DR GO; GO:0007005; P:mitochondrion organization; IEA:Ensembl.
DR GO; GO:0046716; P:muscle cell cellular homeostasis; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0040015; P:negative regulation of multicellular organism growth; IEA:Ensembl.
DR GO; GO:0046621; P:negative regulation of organ growth; IEA:Ensembl.
DR GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; IMP:UniProtKB.
DR GO; GO:0035265; P:organ growth; IEA:Ensembl.
DR GO; GO:0006119; P:oxidative phosphorylation; IEA:Ensembl.
DR GO; GO:1904234; P:positive regulation of aconitate hydratase activity; IMP:BHF-UCL.
DR GO; GO:0043085; P:positive regulation of catalytic activity; IMP:BHF-UCL.
DR GO; GO:0030307; P:positive regulation of cell growth; IMP:BHF-UCL.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:BHF-UCL.
DR GO; GO:0051349; P:positive regulation of lyase activity; IDA:UniProtKB.
DR GO; GO:1904231; P:positive regulation of succinate dehydrogenase activity; IMP:BHF-UCL.
DR GO; GO:0019230; P:proprioception; IEA:Ensembl.
DR GO; GO:0016540; P:protein autoprocessing; IDA:BHF-UCL.
DR GO; GO:0010722; P:regulation of ferrochelatase activity; IDA:BHF-UCL.
DR GO; GO:0010039; P:response to iron ion; IMP:BHF-UCL.
DR DisProt; DP00607; -.
DR Gene3D; 3.30.920.10; -; 1.
DR InterPro; IPR017789; Frataxin.
DR InterPro; IPR002908; Frataxin/CyaY.
DR InterPro; IPR036524; Frataxin/CyaY_sf.
DR InterPro; IPR020895; Frataxin_CS.
DR PANTHER; PTHR16821; PTHR16821; 1.
DR Pfam; PF01491; Frataxin_Cyay; 1.
DR PRINTS; PR00904; FRATAXIN.
DR SMART; SM01219; Frataxin_Cyay; 1.
DR SUPFAM; SSF55387; SSF55387; 1.
DR TIGRFAMs; TIGR03421; FeS_CyaY; 1.
DR TIGRFAMs; TIGR03422; mito_frataxin; 1.
DR PROSITE; PS01344; FRATAXIN_1; 1.
DR PROSITE; PS50810; FRATAXIN_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Direct protein sequencing;
KW Disease variant; Heme biosynthesis; Ion transport; Iron; Iron storage;
KW Iron transport; Metal-binding; Mitochondrion; Oxidoreductase;
KW Reference proteome; Transit peptide; Transport; Triplet repeat expansion.
FT TRANSIT 1..41
FT /note="Mitochondrion"
FT CHAIN 42..210
FT /note="Frataxin intermediate form"
FT /id="PRO_0000010129"
FT CHAIN 56..210
FT /note="Frataxin(56-210)"
FT /id="PRO_0000010130"
FT CHAIN 78..210
FT /note="Frataxin(78-210)"
FT /id="PRO_0000399388"
FT CHAIN 81..210
FT /note="Frataxin mature form"
FT /id="PRO_0000289331"
FT VAR_SEQ 161..210
FT /note="SGPKRYDWTGKNWVYSHDGVSLHELLAAELTKALKTKLDLSSLAYSGKDA
FT -> RLTWLLWLFHP (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:8596916"
FT /id="VSP_001576"
FT VAR_SEQ 161..210
FT /note="SGPKRYDWTGKNWVYSHDGVSLHELLAAELTKALKTKLDLSSLAYSGKDA
FT -> RYVVDLSVMTGLGKTGCTPTTACPSMSCWPQSSLKP (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_047282"
FT VARIANT 106
FT /note="L -> S (in FRDA; dbSNP:rs104894105)"
FT /evidence="ECO:0000269|PubMed:9779809"
FT /id="VAR_016065"
FT VARIANT 122
FT /note="D -> Y (in FRDA; dbSNP:rs142157346)"
FT /evidence="ECO:0000269|PubMed:9989622, ECO:0000269|Ref.7,
FT ECO:0000269|Ref.8"
FT /id="VAR_002428"
FT VARIANT 130
FT /note="G -> V (in FRDA; dbSNP:rs104894107)"
FT /evidence="ECO:0000269|PubMed:10732799,
FT ECO:0000269|PubMed:9150176, ECO:0000269|PubMed:9989622"
FT /id="VAR_002429"
FT VARIANT 154
FT /note="I -> F (in FRDA; reduces interaction with LYRM4; the
FT interaction is rescued by nickel; a murine cellular FRDA
FT model, deleted for endogenous frataxin and expressing human
FT mutant frataxin cDNA shows defects in mitochondrial
FT structure, mitochondrial iron deposits, decreased enzymatic
FT activity of some mitochondrial and cytoplasmic iron-sulfur
FT cluster-containing enzymes, increased RNA-binding activity
FT of ACO1 and increased sensitivity to oxidative stress;
FT dbSNP:rs104894106)"
FT /evidence="ECO:0000269|PubMed:17331979,
FT ECO:0000269|PubMed:19629184, ECO:0000269|PubMed:8596916,
FT ECO:0000269|PubMed:9150176"
FT /id="VAR_002430"
FT VARIANT 155
FT /note="W -> R (in FRDA; reduces interaction with LYRM4; the
FT interaction is rescued by nickel; dbSNP:rs138471431)"
FT /evidence="ECO:0000269|PubMed:17331979, ECO:0000269|Ref.36"
FT /id="VAR_002431"
FT VARIANT 165
FT /note="R -> C (in FRDA; mild form; dbSNP:rs138034837)"
FT /evidence="ECO:0000269|PubMed:10732799"
FT /id="VAR_008139"
FT VARIANT 182
FT /note="L -> F (in FRDA; dbSNP:rs139616452)"
FT /evidence="ECO:0000269|PubMed:10732799"
FT /id="VAR_008140"
FT VARIANT 198
FT /note="L -> R (in FRDA; dbSNP:rs144104124)"
FT /evidence="ECO:0000269|PubMed:10874325"
FT /id="VAR_016066"
FT VARIANT 202
FT /note="S -> C (in dbSNP:rs1052195)"
FT /id="VAR_049100"
FT MUTAGEN 39..40
FT /note="RR->GG: Abolishes cleavage to yield frataxin
FT intermediate form and allows accumulation of frataxin(56-
FT 210) and frataxin(78-210)."
FT /evidence="ECO:0000269|PubMed:18725397"
FT MUTAGEN 53..54
FT /note="RR->GG: No effect on processing of wild-type FXN."
FT /evidence="ECO:0000269|PubMed:17468497,
FT ECO:0000269|PubMed:18725397"
FT MUTAGEN 78..79
FT /note="LR->GG: Abolishes cleavage to yield frataxin mature
FT form and allows accumulation of frataxin(56-210) and
FT frataxin(78-210)."
FT /evidence="ECO:0000269|PubMed:18725397"
FT MUTAGEN 79..80
FT /note="RK->GG: Abolishes cleavage to yield frataxin mature
FT form and allows the accumulation of frataxin(56-210)."
FT /evidence="ECO:0000269|PubMed:17468497,
FT ECO:0000269|PubMed:18725397"
FT CONFLICT 175
FT /note="Y -> F (in Ref. 1; AAA98508/AAA98510)"
FT /evidence="ECO:0000305"
FT CONFLICT 202
FT /note="S -> W (in Ref. 1; AAA98508/AAA98510)"
FT /evidence="ECO:0000305"
FT HELIX 92..114
FT /evidence="ECO:0007829|PDB:3T3L"
FT STRAND 124..128
FT /evidence="ECO:0007829|PDB:3T3L"
FT STRAND 131..135
FT /evidence="ECO:0007829|PDB:3T3L"
FT STRAND 138..140
FT /evidence="ECO:0007829|PDB:6NZU"
FT STRAND 142..148
FT /evidence="ECO:0007829|PDB:3T3L"
FT TURN 149..152
FT /evidence="ECO:0007829|PDB:3T3L"
FT STRAND 153..157
FT /evidence="ECO:0007829|PDB:3T3L"
FT STRAND 159..161
FT /evidence="ECO:0007829|PDB:3T3L"
FT STRAND 164..168
FT /evidence="ECO:0007829|PDB:3T3L"
FT STRAND 170..175
FT /evidence="ECO:0007829|PDB:3T3L"
FT TURN 176..178
FT /evidence="ECO:0007829|PDB:3T3L"
FT HELIX 182..194
FT /evidence="ECO:0007829|PDB:3T3L"
FT STRAND 203..205
FT /evidence="ECO:0007829|PDB:6NZU"
FT STRAND 206..208
FT /evidence="ECO:0007829|PDB:1LY7"
SQ SEQUENCE 210 AA; 23135 MW; ECC81738779308CF CRC64;
MWTLGRRAVA GLLASPSPAQ AQTLTRVPRP AELAPLCGRR GLRTDIDATC TPRRASSNQR
GLNQIWNVKK QSVYLMNLRK SGTLGHPGSL DETTYERLAE ETLDSLAEFF EDLADKPYTF
EDYDVSFGSG VLTVKLGGDL GTYVINKQTP NKQIWLSSPS SGPKRYDWTG KNWVYSHDGV
SLHELLAAEL TKALKTKLDL SSLAYSGKDA
