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 27-MAR-2024, entry version 225. DE RecName: Full=Frataxin, mitochondrial {ECO:0000303|PubMed:18725397}; DE EC=1.16.3.1 {ECO:0000269|PubMed:15641778}; 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 Contains: DE RecName: Full=Extramitochondrial frataxin {ECO:0000303|PubMed:20053667}; DE Flags: Precursor; GN Name=FXN {ECO:0000312|HGNC:HGNC:3951}; 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, PROTEOLYTIC PROCESSING, FUNCTION, INTERACTION RP WITH ACO1, AND SUBCELLULAR 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 (ISOFORM 2), SUBCELLULAR LOCATION, AND FUNCTION. 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 COMPONENT OF CORE (FE-S) CLUSTER ASSEMBLY COMPLEX, MUTAGENESIS OF GLU-96; RP ASP-104; GLU-108; GLU-111; ASP-115; ASP-122; ASP-124; GLY-130; ASN-146; RP ILE-154 AND TRP-173, SUBCELLULAR LOCATION, AND PROTEOLYTIC PROCESSING. RX PubMed=21298097; DOI=10.1371/journal.pone.0016199; RA Schmucker S., Martelli A., Colin F., Page A., Wattenhofer-Donze M., RA Reutenauer L., Puccio H.; RT "Mammalian frataxin: an essential function for cellular viability through RT an interaction with a preformed ISCU/NFS1/ISD11 iron-sulfur assembly RT complex."; RL PLoS ONE 6:e16199-e16199(2011). RN [29] RP VARIANTS FRDA PHE-154; ARG-155 AND CYS-165, CHARACTERIZATION OF VARIANTS RP FRDA PHE-154; ARG-155 AND CYS-165, AND FUNCTION. RX PubMed=24971490; DOI=10.1021/bi500532e; RA Bridwell-Rabb J., Fox N.G., Tsai C.L., Winn A.M., Barondeau D.P.; RT "Human frataxin activates Fe-S cluster biosynthesis by facilitating sulfur RT transfer chemistry."; RL Biochemistry 53:4904-4913(2014). RN [30] 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 [31] 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 [32] RP INTERACTION WITH THE CYSTEINE DESULFURASE COMPLEX AND ISCU, AND FUNCTION. RX PubMed=29576242; DOI=10.1016/j.jinorgbio.2018.03.007; RA Cai K., Frederick R.O., Tonelli M., Markley J.L.; RT "Interactions of iron-bound frataxin with ISCU and ferredoxin on the RT cysteine desulfurase complex leading to Fe-S cluster assembly."; RL J. Inorg. Biochem. 183:107-116(2018). RN [33] 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 [34] 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 [35] {ECO:0007744|PDB:6NZU} RP STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS) OF 81-210 IN COMPLEX WITH RP ISCU; LYRM4 AND FNS1, SUBUNIT, VARIANTS FRDA ARG-155 AND CYS-165, RP CHARACTERIZATION OF VARIANTS FRDA ARG-155 AND CYS-165, AND INTERACTION WITH RP ISCU. RX PubMed=31101807; DOI=10.1038/s41467-019-09989-y; RA Fox N.G., Yu X., Feng X., Bailey H.J., Martelli A., Nabhan J.F., RA Strain-Damerell C., Bulawa C., Yue W.W., Han S.; RT "Structure of the human frataxin-bound iron-sulfur cluster assembly complex RT provides insight into its activation mechanism."; RL Nat. Commun. 10:2210-2210(2019). RN [36] 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 [37] RP VARIANT FRDA SER-106. RX PubMed=9779809; RX DOI=10.1002/(sici)1096-8628(19981012)79:5<396::aid-ajmg13>3.3.co;2-b; 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 [38] 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 [39] 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 [40] 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 [41] 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 [42] 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: [Frataxin mature form]: Functions as an activator of CC persulfide transfer to the scaffoding protein ISCU as component of the CC core iron-sulfur cluster (ISC) assembly complex and participates to the CC [2Fe-2S] cluster assembly (PubMed:24971490, PubMed:12785837). CC Accelerates sulfur transfer from NFS1 persulfide intermediate to ISCU CC and to small thiols such as L-cysteine and glutathione leading to CC persulfuration of these thiols and ultimately sulfide release CC (PubMed:24971490). Binds ferrous ion and is released from FXN upon the CC addition of both L-cysteine and reduced FDX2 during [2Fe-2S] cluster CC assembly (PubMed:29576242). The core iron-sulfur cluster (ISC) assembly CC complex is involved in the de novo synthesis of a [2Fe-2S] cluster, the CC first step of the mitochondrial iron-sulfur protein biogenesis. This CC process is initiated by the cysteine desulfurase complex CC (NFS1:LYRM4:NDUFAB1) that produces persulfide which is delivered on the CC scaffold protein ISCU in a FXN-dependent manner. Then this complex is CC stabilized by FDX2 which provides reducing equivalents to accomplish CC the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S] cluster is CC transferred from ISCU to chaperone proteins, including HSCB, HSPA9 and CC GLRX5 (By similarity). May play a role in the protection against iron- CC catalyzed oxidative stress through its ability to catalyze the CC oxidation of Fe(2+) to Fe(3+); the oligomeric form but not the CC monomeric form has in vitro ferroxidase activity (PubMed:15641778). May CC be able to store large amounts of iron in the form of a ferrihydrite CC mineral by oligomerization; however, the physiological relevance is CC unsure as reports are conflicting and the function has only been shown CC using heterologous overexpression systems (PubMed:11823441, CC PubMed:12755598). May function as an iron chaperone protein that CC protects the aconitase [4Fe-4S]2+ cluster from disassembly and promotes CC enzyme reactivation (PubMed:15247478). May play a role as a high CC affinity iron binding partner for FECH that is capable of both CC delivering iron to ferrochelatase and mediating the terminal step in CC mitochondrial heme biosynthesis (PubMed:15123683, PubMed:16239244). CC {ECO:0000250|UniProtKB:Q9H1K1, ECO:0000269|PubMed:11823441, CC ECO:0000269|PubMed:12755598, ECO:0000269|PubMed:12785837, CC ECO:0000269|PubMed:15123683, ECO:0000269|PubMed:15247478, CC ECO:0000269|PubMed:15641778, ECO:0000269|PubMed:16239244, CC ECO:0000269|PubMed:24971490, ECO:0000269|PubMed:29576242}. CC -!- FUNCTION: [Extramitochondrial frataxin]: Modulates the RNA-binding CC activity of ACO1 (PubMed:20053667). May be involved in the cytoplasmic CC iron-sulfur protein biogenesis (PubMed:16091420). May contribute to CC oxidative stress resistance and overall cell survival CC (PubMed:16608849). {ECO:0000269|PubMed:16091420, CC ECO:0000269|PubMed:16608849, ECO:0000269|PubMed:20053667}. CC -!- CATALYTIC ACTIVITY: [Frataxin mature form]: 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: [Frataxin mature form]: Component of the mitochondrial core CC iron-sulfur cluster (ISC) complex composed of NFS1, LYRM4, NDUFAB1, CC ISCU, FXN, and FDX2; this complex is an heterohexamer containing two CC copies of each monomer (Probable). Homodimer (PubMed:31101807). Monomer CC (probable predominant form). Oligomer. Monomers and polymeric CC aggregates of >1 MDa have been isolated from mitochondria. A small CC fraction of heterologous overexpressed recombinant frataxin forms high- CC molecular weight aggregates that incorporate iron (PubMed:11823441, CC PubMed:12755598, PubMed:15641778, PubMed:15581888). Interacts with CC LYRM4 (PubMed:17331979). Interacts (via ferrous form) with ISCU; the CC interaction is possible when both are bound to the dimeric form of the CC cysteine desulfurase complex (NFS1:LYRM4) and the interaction enhances CC FXN interaction to the dimeric form of the cysteine desulfurase complex CC (NFS1:LYRM4)(PubMed:12785837, PubMed:31101807, PubMed:29576242). CC Interacts with FECH; one iron-bound FXN monomer seems to interact with CC a FECH homodimer (PubMed:15123683). Interacts with SDHA and SDHB CC (PubMed:15961414). Interacts with ACO2; the interaction is dependent on CC citrate (By similarity). Interacts with HSPA9 (PubMed:17331979, CC PubMed:26702583). {ECO:0000250|UniProtKB:D3ZYW7, CC ECO:0000269|PubMed:11823441, ECO:0000269|PubMed:12755598, CC ECO:0000269|PubMed:12785837, ECO:0000269|PubMed:15123683, CC ECO:0000269|PubMed:15581888, ECO:0000269|PubMed:15641778, CC ECO:0000269|PubMed:15961414, ECO:0000269|PubMed:17331979, CC ECO:0000269|PubMed:26702583, ECO:0000269|PubMed:29576242, CC ECO:0000269|PubMed:31101807, ECO:0000305|PubMed:21298097, CC ECO:0000305|PubMed:31101807}. CC -!- SUBUNIT: [Extramitochondrial frataxin]: Interacts with ACO1 CC (PubMed:20053667). Interacts with ISCU (cytoplasmic form) CC (PubMed:16091420). {ECO:0000269|PubMed:16091420, CC ECO:0000269|PubMed:20053667}. 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: SKIC8; NbExp=3; IntAct=EBI-949340, EBI-358545; CC -!- SUBCELLULAR LOCATION: [Frataxin mature form]: Mitochondrion CC {ECO:0000269|PubMed:15581888, ECO:0000269|PubMed:16091420, CC ECO:0000269|PubMed:16608849, ECO:0000269|PubMed:18725397, CC ECO:0000269|PubMed:20053667, ECO:0000269|PubMed:21298097, CC ECO:0000269|PubMed:9241270, ECO:0000269|PubMed:9302253}. CC -!- SUBCELLULAR LOCATION: [Extramitochondrial frataxin]: Cytoplasm, cytosol CC {ECO:0000269|PubMed:16091420, ECO:0000269|PubMed:16608849, CC ECO:0000269|PubMed:20053667}. 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 (PubMed:21298097). The CC additional forms, frataxin(56-210) and frataxin(78-210), seem to be CC produced when the normal maturation process is impaired; their CC physiological relevance is unsure. {ECO:0000269|PubMed:10428860, CC ECO:0000269|PubMed:10545606, ECO:0000269|PubMed:11020385, CC ECO:0000269|PubMed:17468497, ECO:0000269|PubMed:18725397, CC ECO:0000269|PubMed:21298097}. 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:24971490, ECO:0000269|PubMed:31101807, CC ECO:0000269|PubMed:9150176, ECO:0000269|PubMed:9779809, CC ECO:0000269|PubMed:9989622, ECO:0000269|Ref.40, 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 EMDB; EMD-0560; -. DR EMDB; EMD-8301; -. DR SASBDB; Q16595; -. DR SMR; Q16595; -. DR BioGRID; 108677; 57. DR ComplexPortal; CPX-5641; Mitochondrial NIAUFX iron-sulfur cluster assembly complex. DR CORUM; Q16595; -. DR IntAct; Q16595; 23. DR MINT; Q16595; -. DR STRING; 9606.ENSP00000419243; -. 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; 9606-ENSP00000366482; -. DR PeptideAtlas; Q16595; -. DR ProteomicsDB; 2327; -. DR ProteomicsDB; 60939; -. [Q16595-1] DR ProteomicsDB; 60940; -. [Q16595-2] DR Pumba; Q16595; -. DR TopDownProteomics; Q16595-1; -. [Q16595-1] DR TopDownProteomics; Q16595-2; -. [Q16595-2] DR ABCD; Q16595; 1 sequenced antibody. DR Antibodypedia; 26793; 729 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 AGR; HGNC:3951; -. 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 HOGENOM; CLU_080880_1_0_1; -. DR InParanoid; Q16595; -. DR OMA; QSVHLMN; -. DR OrthoDB; 198155at2759; -. 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 SABIO-RK; Q16595; -. DR SignaLink; Q16595; -. DR SIGNOR; Q16595; -. DR BioGRID-ORCS; 2395; 504 hits in 1139 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 181 other cell types or tissues. DR ExpressionAtlas; Q16595; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:BHF-UCL. DR GO; GO:1990229; C:iron-sulfur cluster assembly complex; NAS:ComplexPortal. DR GO; GO:1990221; C:L-cysteine desulfurase complex; IDA:FlyBase. DR GO; GO:0099128; C:mitochondrial iron-sulfur cluster assembly complex; IDA:UniProtKB. DR GO; GO:0005759; C:mitochondrial matrix; ISS:BHF-UCL. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. 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:UniProtKB. DR GO; GO:0004322; F:ferroxidase activity; IDA:UniProtKB. DR GO; GO:0034986; F:iron chaperone activity; IDA:BHF-UCL. DR GO; GO:0044571; P:[2Fe-2S] cluster assembly; IDA:UniProtKB. DR GO; GO:0044572; P:[4Fe-4S] cluster assembly; IDA:UniProtKB. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. 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:0006879; P:intracellular iron ion homeostasis; IMP:BHF-UCL. DR GO; GO:0018283; P:iron incorporation into metallo-sulfur cluster; IDA:BHF-UCL. DR GO; GO:0006826; P:iron ion transport; IEA:UniProtKB-KW. 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 CDD; cd00503; Frataxin; 1. DR DisProt; DP00607; -. DR Gene3D; 3.30.920.10; Frataxin/CyaY; 1. DR InterPro; IPR017789; Frataxin. DR InterPro; IPR002908; Frataxin/CyaY. DR InterPro; IPR036524; Frataxin/CyaY_sf. DR InterPro; IPR020895; Frataxin_CS. DR NCBIfam; TIGR03421; FeS_CyaY; 1. DR NCBIfam; TIGR03422; mito_frataxin; 1. DR PANTHER; PTHR16821; FRATAXIN; 1. DR PANTHER; PTHR16821:SF4; FRATAXIN, MITOCHONDRIAL; 1. DR Pfam; PF01491; Frataxin_Cyay; 1. DR PRINTS; PR00904; FRATAXIN. DR SMART; SM01219; Frataxin_Cyay; 1. DR SUPFAM; SSF55387; Frataxin/Nqo15-like; 1. DR PROSITE; PS01344; FRATAXIN_1; 1. DR PROSITE; PS50810; FRATAXIN_2; 1. DR Genevisible; Q16595; HS. 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="Extramitochondrial frataxin" FT /id="PRO_0000456947" 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 decreases the level of covalent incorporation of sulfur FT into both NFS1 and ISCU; dbSNP:rs104894106)" FT /evidence="ECO:0000269|PubMed:17331979, FT ECO:0000269|PubMed:19629184, ECO:0000269|PubMed:24971490, FT ECO:0000269|PubMed:8596916, ECO:0000269|PubMed:9150176" FT /id="VAR_087120" FT VARIANT 155 FT /note="W -> R (in FRDA; reduces interaction with LYRM4; the FT interaction is rescued by nickel; drastically decreases FT affinity for the SDAU complex by > 75-fold; decreases the FT level of covalent incorporation of sulfur into both NFS1 FT and ISCU; dbSNP:rs138471431)" FT /evidence="ECO:0000269|PubMed:17331979, FT ECO:0000269|PubMed:24971490, ECO:0000269|PubMed:31101807, FT ECO:0000269|Ref.40" FT /id="VAR_087121" FT VARIANT 165 FT /note="R -> C (in FRDA; mild form; decreases affinity for FT the SDAU complex by 40-fold; decreases the level of FT covalent incorporation of sulfur into both NFS1 and ISCU; FT dbSNP:rs138034837)" FT /evidence="ECO:0000269|PubMed:10732799, FT ECO:0000269|PubMed:24971490, ECO:0000269|PubMed:31101807" FT /id="VAR_087122" 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 FT frataxin(56-210) 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 MUTAGEN 96 FT /note="E->K: Does not affect interaction with the core FT iron-sulfur cluster assembly complex. Does not affect FT mitochondrial localization. Does not affect proteolytic FT processing." FT /evidence="ECO:0000269|PubMed:21298097" FT MUTAGEN 104 FT /note="D->G: Does not affect interaction with the core FT iron-sulfur cluster assembly complex. Does not affect FT mitochondrial localization. Does not affect proteolytic FT processing." FT /evidence="ECO:0000269|PubMed:21298097" FT MUTAGEN 108 FT /note="E->K: Significantly reduces interaction with the FT core iron-sulfur cluster assembly complex. Does not affect FT mitochondrial localization. Does not affect proteolytic FT processing." FT /evidence="ECO:0000269|PubMed:21298097" FT MUTAGEN 111 FT /note="E->K: Significantly reduces interaction with the FT core iron-sulfur cluster assembly complex. Does not affect FT mitochondrial localization. Does not affect proteolytic FT processing." FT /evidence="ECO:0000269|PubMed:21298097" FT MUTAGEN 115 FT /note="D->K: Does not affect interaction with the core FT iron-sulfur cluster assembly complex. Does not affect FT mitochondrial localization. Does not affect proteolytic FT processing." FT /evidence="ECO:0000269|PubMed:21298097" FT MUTAGEN 122 FT /note="D->Y: Does not affect interaction with the core FT iron-sulfur cluster assembly complex. Does not affect FT mitochondrial localization. Does not affect proteolytic FT processing." FT /evidence="ECO:0000269|PubMed:21298097" FT MUTAGEN 124 FT /note="D->K: Drasticly reduces interaction with the core FT iron-sulfur cluster assembly complex. Does not affect FT mitochondrial localization. Does not affect proteolytic FT processing." FT /evidence="ECO:0000269|PubMed:21298097" FT MUTAGEN 130 FT /note="G->V: Does not affect interaction with the core FT iron-sulfur cluster assembly complex. Does not affect FT mitochondrial localization. Does not affect proteolytic FT processing." FT /evidence="ECO:0000269|PubMed:21298097" FT MUTAGEN 146 FT /note="N->A: Does not affect interaction with the core FT iron-sulfur cluster assembly complex. Does not affect FT mitochondrial localization. Does not affect proteolytic FT processing." FT /evidence="ECO:0000269|PubMed:21298097" FT MUTAGEN 154 FT /note="I->F: Reduces interaction with the core iron-sulfur FT cluster assembly complex. Does not affect mitochondrial FT localization. Does not affect proteolytic processing." FT /evidence="ECO:0000269|PubMed:21298097" FT MUTAGEN 173 FT /note="W->G: Loss of interaction with the core iron-sulfur FT cluster assembly complex. Does not affect mitochondrial FT localization. Does not affect proteolytic processing." FT /evidence="ECO:0000269|PubMed:21298097" 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 //