ID   FRDA_RAT                Reviewed;         208 AA.
AC   D3ZYW7;
DT   05-OCT-2010, integrated into UniProtKB/Swiss-Prot.
DT   20-APR-2010, sequence version 1.
DT   27-MAR-2024, entry version 67.
DE   RecName: Full=Frataxin, mitochondrial {ECO:0000303|PubMed:15247478};
DE            Short=Fxn;
DE            EC=1.16.3.1 {ECO:0000250|UniProtKB:Q16595};
DE   Contains:
DE     RecName: Full=Frataxin intermediate form;
DE   Contains:
DE     RecName: Full=Frataxin mature form;
DE   Contains:
DE     RecName: Full=Extramitochondrial frataxin {ECO:0000250|UniProtKB:Q16595};
DE   Flags: Precursor;
GN   Name=Fxn {ECO:0000312|RGD:1565754};
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=Brown Norway;
RX   PubMed=15057822; DOI=10.1038/nature02426;
RA   Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA   Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA   Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA   Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA   Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA   Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA   Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T., Smith D.,
RA   Lee H.-M., Gustafson E., Cahill P., Kana A., Doucette-Stamm L.,
RA   Weinstock K., Fechtel K., Weiss R.B., Dunn D.M., Green E.D.,
RA   Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K., Zhu B., Marra M.,
RA   Schein J., Bosdet I., Fjell C., Jones S., Krzywinski M., Mathewson C.,
RA   Siddiqui A., Wye N., McPherson J., Zhao S., Fraser C.M., Shetty J.,
RA   Shatsman S., Geer K., Chen Y., Abramzon S., Nierman W.C., Havlak P.H.,
RA   Chen R., Durbin K.J., Egan A., Ren Y., Song X.-Z., Li B., Liu Y., Qin X.,
RA   Cawley S., Cooney A.J., D'Souza L.M., Martin K., Wu J.Q.,
RA   Gonzalez-Garay M.L., Jackson A.R., Kalafus K.J., McLeod M.P.,
RA   Milosavljevic A., Virk D., Volkov A., Wheeler D.A., Zhang Z., Bailey J.A.,
RA   Eichler E.E., Tuzun E., Birney E., Mongin E., Ureta-Vidal A., Woodwark C.,
RA   Zdobnov E., Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA   Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D., Schmidt J.,
RA   Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M., Abril J.F.,
RA   Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O., Poliakov A.,
RA   Huebner N., Ganten D., Goesele C., Hummel O., Kreitler T., Lee Y.-A.,
RA   Monti J., Schulz H., Zimdahl H., Himmelbauer H., Lehrach H., Jacob H.J.,
RA   Bromberg S., Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E.,
RA   Lazar J., Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA   Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E., Webber C.,
RA   Brandt P., Nyakatura G., Adetobi M., Chiaromonte F., Elnitski L.,
RA   Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K., Miller W.,
RA   Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S., Zhang Y.,
RA   Lindpaintner K., Andrews T.D., Caccamo M., Clamp M., Clarke L., Curwen V.,
RA   Durbin R.M., Eyras E., Searle S.M., Cooper G.M., Batzoglou S., Brudno M.,
RA   Sidow A., Stone E.A., Payseur B.A., Bourque G., Lopez-Otin C., Puente X.S.,
RA   Chakrabarti K., Chatterji S., Dewey C., Pachter L., Bray N., Yap V.B.,
RA   Caspi A., Tesler G., Pevzner P.A., Haussler D., Roskin K.M., Baertsch R.,
RA   Clawson H., Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J.,
RA   Rosenbloom K.R., Trumbower H., Weirauch M., Cooper D.N., Stenson P.D.,
RA   Ma B., Brent M., Arumugam M., Shteynberg D., Copley R.R., Taylor M.S.,
RA   Riethman H., Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S.,
RA   Mockrin S., Collins F.S.;
RT   "Genome sequence of the Brown Norway rat yields insights into mammalian
RT   evolution.";
RL   Nature 428:493-521(2004).
RN   [2]
RP   FUNCTION AS IRON CHAPERONE, AND INTERACTION WITH ACO2.
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).
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. Accelerates sulfur transfer from NFS1
CC       persulfide intermediate to ISCU and to small thiols such as L-cysteine
CC       and glutathione leading to persulfuration of these thiols and
CC       ultimately sulfide release. Binds ferrous ion and is released from FXN
CC       upon the addition of both L-cysteine and reduced FDX2 during [2Fe-2S]
CC       cluster assembly (By similarity). The core iron-sulfur cluster (ISC)
CC       assembly complex is involved in the de novo synthesis of a [2Fe-2S]
CC       cluster, the first step of the mitochondrial iron-sulfur protein
CC       biogenesis. This process is initiated by the cysteine desulfurase
CC       complex (NFS1:LYRM4:NDUFAB1) that produces persulfide which is
CC       delivered on the scaffold protein ISCU in a FXN-dependent manner. Then
CC       this complex is stabilized by FDX2 which provides reducing equivalents
CC       to accomplish the [2Fe-2S] cluster assembly. Finally, the [2Fe-2S]
CC       cluster is transferred from ISCU to chaperone proteins, including HSCB,
CC       HSPA9 and GLRX5 (By similarity). May play a role in the protection
CC       against iron-catalyzed oxidative stress through its ability to catalyze
CC       the oxidation of Fe(2+) to Fe(3+); the oligomeric form but not the
CC       monomeric form has in vitro ferroxidase activity. May be able to store
CC       large amounts of iron in the form of a ferrihydrite mineral by
CC       oligomerization; however, the physiological relevance is unsure as
CC       reports are conflicting and the function has only been shown using
CC       heterologous overexpression systems (By similarity). May function as an
CC       iron chaperone protein that protects the aconitase [4Fe-4S]2+ cluster
CC       from disassembly and promotes enzyme reactivation (PubMed:15247478).
CC       May play a role as a high affinity iron binding partner for FECH that
CC       is capable of both delivering iron to ferrochelatase and mediating the
CC       terminal step in mitochondrial heme biosynthesis (By similarity).
CC       {ECO:0000250|UniProtKB:Q16595, ECO:0000250|UniProtKB:Q9H1K1,
CC       ECO:0000269|PubMed:15247478}.
CC   -!- FUNCTION: [Extramitochondrial frataxin]: Modulates the RNA-binding
CC       activity of ACO1. May be involved in the cytoplasmic iron-sulfur
CC       protein biogenesis. May contribute to oxidative stress resistance and
CC       overall cell survival. {ECO:0000250|UniProtKB:Q16595}.
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:0000250|UniProtKB:Q16595};
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. Homodimer. Monomer (probable predominant form).
CC       Oligomer. Monomers and polymeric aggregates of >1 MDa have been
CC       isolated from mitochondria. A small fraction of heterologous
CC       overexpressed recombinant frataxin forms high-molecular weight
CC       aggregates that incorporate iron. Interacts with LYRM4. Interacts (via
CC       ferrous form) with ISCU; the interaction is possible when both are
CC       bound to the dimeric form of the cysteine desulfurase complex
CC       (NFS1:LYRM4) and the interaction enhances FXN interaction to the
CC       dimeric form of the cysteine desulfurase complex (NFS1:LYRM4) (By
CC       similarity). Interacts with FECH; one iron-bound FXN monomer seems to
CC       interact with a FECH homodimer. Interacts with SDHA and SDHB (By
CC       similarity). Interacts with ACO2; the interaction is dependent on
CC       citrate (PubMed:15247478). Interacts with HSPA9 (By similarity).
CC       {ECO:0000250|UniProtKB:Q16595, ECO:0000269|PubMed:15247478}.
CC   -!- SUBUNIT: [Extramitochondrial frataxin]: Interacts with ACO1. Interacts
CC       with ISCU (cytoplasmic form). {ECO:0000250|UniProtKB:Q16595}.
CC   -!- SUBCELLULAR LOCATION: [Frataxin mature form]: Mitochondrion
CC       {ECO:0000250|UniProtKB:Q16595}.
CC   -!- SUBCELLULAR LOCATION: [Extramitochondrial frataxin]: Cytoplasm, cytosol
CC       {ECO:0000250|UniProtKB:Q16595}.
CC   -!- PTM: [Frataxin mature form]: Processed in two steps by mitochondrial
CC       processing peptidase (MPP). MPP first cleaves the precursor to
CC       intermediate form and subsequently converts the intermediate to yield
CC       frataxin mature form (frataxin(81-210)) which is the predominant form.
CC       The 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:0000250|UniProtKB:Q16595}.
CC   -!- SIMILARITY: Belongs to the frataxin family. {ECO:0000305}.
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DR   EMBL; AABR03005338; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AABR03006217; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AABR03009513; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   AlphaFoldDB; D3ZYW7; -.
DR   SMR; D3ZYW7; -.
DR   STRING; 10116.ENSRNOP00000020412; -.
DR   iPTMnet; D3ZYW7; -.
DR   PhosphoSitePlus; D3ZYW7; -.
DR   PaxDb; 10116-ENSRNOP00000020412; -.
DR   PeptideAtlas; D3ZYW7; -.
DR   UCSC; RGD:1565754; rat.
DR   AGR; RGD:1565754; -.
DR   RGD; 1565754; Fxn.
DR   eggNOG; KOG3413; Eukaryota.
DR   InParanoid; D3ZYW7; -.
DR   PhylomeDB; D3ZYW7; -.
DR   TreeFam; TF318958; -.
DR   Reactome; R-RNO-1268020; Mitochondrial protein import.
DR   Reactome; R-RNO-1362409; Mitochondrial iron-sulfur cluster biogenesis.
DR   PRO; PR:D3ZYW7; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0005829; C:cytosol; ISO:RGD.
DR   GO; GO:1990221; C:L-cysteine desulfurase complex; ISO:RGD.
DR   GO; GO:0099128; C:mitochondrial iron-sulfur cluster assembly complex; ISS:UniProtKB.
DR   GO; GO:0005739; C:mitochondrion; IDA:RGD.
DR   GO; GO:0051537; F:2 iron, 2 sulfur cluster binding; ISO:RGD.
DR   GO; GO:0019899; F:enzyme binding; IPI:RGD.
DR   GO; GO:0008199; F:ferric iron binding; ISO:RGD.
DR   GO; GO:0008198; F:ferrous iron binding; ISO:RGD.
DR   GO; GO:0004322; F:ferroxidase activity; ISO:RGD.
DR   GO; GO:0034986; F:iron chaperone activity; ISO:RGD.
DR   GO; GO:0016530; F:metallochaperone activity; NAS:RGD.
DR   GO; GO:0044571; P:[2Fe-2S] cluster assembly; ISS:UniProtKB.
DR   GO; GO:0044572; P:[4Fe-4S] cluster assembly; ISS:UniProtKB.
DR   GO; GO:0007628; P:adult walking behavior; ISO:RGD.
DR   GO; GO:0009060; P:aerobic respiration; ISO:RGD.
DR   GO; GO:0042149; P:cellular response to glucose starvation; IEP:RGD.
DR   GO; GO:0070301; P:cellular response to hydrogen peroxide; ISO:RGD.
DR   GO; GO:0071456; P:cellular response to hypoxia; IEP:RGD.
DR   GO; GO:0009792; P:embryo development ending in birth or egg hatching; ISO:RGD.
DR   GO; GO:0006783; P:heme biosynthetic process; IEA:UniProtKB-KW.
DR   GO; GO:0006879; P:intracellular iron ion homeostasis; ISO:RGD.
DR   GO; GO:0048250; P:iron import into the mitochondrion; IMP:RGD.
DR   GO; GO:0016226; P:iron-sulfur cluster assembly; ISO:RGD.
DR   GO; GO:0007005; P:mitochondrion organization; ISO:RGD.
DR   GO; GO:0046716; P:muscle cell cellular homeostasis; ISO:RGD.
DR   GO; GO:0043066; P:negative regulation of apoptotic process; ISO:RGD.
DR   GO; GO:0010888; P:negative regulation of lipid storage; IMP:RGD.
DR   GO; GO:0040015; P:negative regulation of multicellular organism growth; ISO:RGD.
DR   GO; GO:0043524; P:negative regulation of neuron apoptotic process; IMP:RGD.
DR   GO; GO:0046621; P:negative regulation of organ growth; ISO:RGD.
DR   GO; GO:0090201; P:negative regulation of release of cytochrome c from mitochondria; ISO:RGD.
DR   GO; GO:0035265; P:organ growth; ISO:RGD.
DR   GO; GO:0006119; P:oxidative phosphorylation; ISO:RGD.
DR   GO; GO:0045773; P:positive regulation of axon extension; IMP:RGD.
DR   GO; GO:0030307; P:positive regulation of cell growth; ISO:RGD.
DR   GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:RGD.
DR   GO; GO:0035794; P:positive regulation of mitochondrial membrane permeability; IMP:RGD.
DR   GO; GO:0019230; P:proprioception; ISO:RGD.
DR   GO; GO:0016540; P:protein autoprocessing; ISO:RGD.
DR   GO; GO:0051480; P:regulation of cytosolic calcium ion concentration; IMP:RGD.
DR   GO; GO:0010039; P:response to iron ion; ISO:RGD.
DR   GO; GO:0014070; P:response to organic cyclic compound; IEP:RGD.
DR   GO; GO:0009410; P:response to xenobiotic stimulus; IEP:RGD.
DR   CDD; cd00503; Frataxin; 1.
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   NCBIfam; TIGR03421; FeS_CyaY; 1.
DR   NCBIfam; TIGR03422; mito_frataxin; 1.
DR   PANTHER; PTHR16821; FRATAXIN; 1.
DR   PANTHER; PTHR16821:SF2; 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; PS50810; FRATAXIN_2; 1.
PE   1: Evidence at protein level;
KW   Cytoplasm; Heme biosynthesis; Ion transport; Iron; Iron storage;
KW   Iron transport; Mitochondrion; Oxidoreductase; Reference proteome;
KW   Transit peptide; Transport.
FT   TRANSIT         1..40
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000250"
FT   CHAIN           41..208
FT                   /note="Frataxin intermediate form"
FT                   /id="PRO_0000399465"
FT   CHAIN           79..208
FT                   /note="Extramitochondrial frataxin"
FT                   /evidence="ECO:0000250|UniProtKB:Q16595"
FT                   /id="PRO_0000456950"
FT   CHAIN           79..208
FT                   /note="Frataxin mature form"
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000399391"
SQ   SEQUENCE   208 AA;  23066 MW;  401B8210F5CEDD35 CRC64;
     MWTFGRRAAA GLLPRTASRA SAWVRNPRGR ERIGTCGRRG LHVTANADAI RHSHLNLHYL
     GQILNIKKQS VCVVHLRNSG TLGNPSSLDE TAYERLAEET LDALAEFFED LADKPYTLKD
     YDVSFGDGVL TIKLGGDLGT YVINKQTPLL YLWFSGPCSG PKRYDWTGKN WVYSHDGVSL
     HELLARELTE ALNTKLDLSS LAYSGKGT
//