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Protein

Frataxin, mitochondrial

Gene

FXN

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Promotes the biosynthesis of heme and assembly and repair of iron-sulfur clusters by delivering Fe2+ to proteins involved in these pathways. May play a role in the protection against iron-catalyzed oxidative stress through its ability to catalyze the oxidation of Fe2+ to Fe3+; the oligomeric form but not the monomeric form has in vitro ferroxidase activity. May be able to store large amounts of iron in the form of a ferrihydrite mineral by oligomerization; however, the physiological relevance is unsure as reports are conflicting and the function has only been shown using heterologous overexpression systems. Modulates the RNA-binding activity of ACO1.6 Publications

Miscellaneous

The unusual migration profile of mature frataxin on SDS-PAGE due to its acidic N-terminus most likely contributed to conflicting reports for the N-terminus of the mature protein. Unlike prokaryotic and yeast frataxin homologs, which self-assemble at high iron concentrations, oligomerization of human frataxin is not induced by iron. The existence of a specialized mitochondrial ferritin in mammalia (FTMT) is suggesting that iron storage would be redundant function, at least in mammalian mitochondria.

Caution

Catalytic activityi

4 Fe2+ + 4 H+ + O2 = 4 Fe3+ + 2 H2O.1 Publication

GO - Molecular functioni

  • 2 iron, 2 sulfur cluster binding Source: BHF-UCL
  • ferric iron binding Source: BHF-UCL
  • ferrous iron binding Source: BHF-UCL
  • ferroxidase activity Source: UniProtKB
  • iron chaperone activity Source: BHF-UCL

GO - Biological processi

  • cellular iron ion homeostasis Source: BHF-UCL
  • cellular response to hydrogen peroxide Source: UniProtKB
  • heme biosynthetic process Source: BHF-UCL
  • ion transport Source: UniProtKB-KW
  • iron incorporation into metallo-sulfur cluster Source: BHF-UCL
  • negative regulation of apoptotic process Source: UniProtKB
  • negative regulation of release of cytochrome c from mitochondria Source: UniProtKB
  • positive regulation of aconitate hydratase activity Source: BHF-UCL
  • positive regulation of catalytic activity Source: BHF-UCL
  • positive regulation of cell growth Source: BHF-UCL
  • positive regulation of cell proliferation Source: BHF-UCL
  • positive regulation of lyase activity Source: UniProtKB
  • positive regulation of succinate dehydrogenase activity Source: BHF-UCL
  • protein autoprocessing Source: BHF-UCL
  • regulation of ferrochelatase activity Source: BHF-UCL
  • response to iron ion Source: BHF-UCL
  • small molecule metabolic process Source: Reactome

Keywordsi

Molecular functionOxidoreductase
Biological processHeme biosynthesis, Ion transport, Iron storage, Iron transport, Transport
LigandIron, Metal-binding

Enzyme and pathway databases

ReactomeiR-HSA-1268020 Mitochondrial protein import
R-HSA-1362409 Mitochondrial iron-sulfur cluster biogenesis

Protein family/group databases

TCDBi9.B.21.1.1 the frataxin (frataxin) family

Names & Taxonomyi

Protein namesi
Recommended name:
Frataxin, mitochondrial (EC:1.16.3.1)
Alternative name(s):
Friedreich ataxia protein
Short name:
Fxn
Cleaved into the following 4 chains:
Alternative name(s):
m56-FXN
Alternative name(s):
d-FXN
m78-FXN
Alternative name(s):
Frataxin(81-210)
m81-FXN
Gene namesi
Name:FXN
Synonyms:FRDA, X25
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 9

Organism-specific databases

EuPathDBiHostDB:ENSG00000165060.11
HGNCiHGNC:3951 FXN
MIMi606829 gene
neXtProtiNX_Q16595

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Mitochondrion

Pathology & Biotechi

Involvement in diseasei

Friedreich ataxia (FRDA)9 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAutosomal recessive, progressive degenerative disease characterized by neurodegeneration and cardiomyopathy it is the most common inherited ataxia. The disorder is usually manifest before adolescence and is generally characterized by incoordination of limb movements, dysarthria, nystagmus, diminished or absent tendon reflexes, Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus, and hammer toe. In most patients, FRDA is due to GAA triplet repeat expansions in the first intron of the frataxin gene. But in some cases the disease is due to mutations in the coding region.
See also OMIM:229300
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_016065106L → S in FRDA. 1 PublicationCorresponds to variant dbSNP:rs104894105Ensembl.1
Natural variantiVAR_002428122D → Y in FRDA. 3 PublicationsCorresponds to variant dbSNP:rs142157346Ensembl.1
Natural variantiVAR_002429130G → V in FRDA. 3 PublicationsCorresponds to variant dbSNP:rs104894107Ensembl.1
Natural variantiVAR_002430154I → F in FRDA; reduces interaction with LYRM4; the interaction is rescued by nickel; a murine cellular FRDA model, deleted for endogenous frataxin and expressing human mutant frataxin cDNA shows defects in mitochondrial structure, mitochondrial iron deposits, decreased enzymatic activity of some mitochondrial and cytoplasmic iron-sulfur cluster-containing enzymes, increased RNA-binding activity of ACO1 and increased sensitivity to oxidative stress. 4 PublicationsCorresponds to variant dbSNP:rs104894106Ensembl.1
Natural variantiVAR_002431155W → R in FRDA; reduces interaction with LYRM4; the interaction is rescued by nickel. 2 PublicationsCorresponds to variant dbSNP:rs138471431Ensembl.1
Natural variantiVAR_008139165R → C in FRDA; mild form. 1 PublicationCorresponds to variant dbSNP:rs138034837Ensembl.1
Natural variantiVAR_008140182L → F in FRDA. 1 PublicationCorresponds to variant dbSNP:rs139616452Ensembl.1
Natural variantiVAR_016066198L → R in FRDA. 1 PublicationCorresponds to variant dbSNP:rs144104124Ensembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi39 – 40RR → GG: Abolishes cleavage to yield frataxin intermediate form and allows accumulation of frataxin(56-210) and frataxin(78-210). 1 Publication2
Mutagenesisi53 – 54RR → GG: No effect on processing of wild-type FXN. 2 Publications2
Mutagenesisi78 – 79LR → GG: Abolishes cleavage to yield frataxin mature form and allows accumulation of frataxin(56-210) and frataxin(78-210). 1 Publication2
Mutagenesisi79 – 80RK → GG: Abolishes cleavage to yield frataxin mature form and allows the accumulation of frataxin(56-210). 2 Publications2

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi2395
GeneReviewsiFXN
MalaCardsiFXN
MIMi229300 phenotype
OpenTargetsiENSG00000165060
Orphaneti95 Friedreich ataxia
PharmGKBiPA28369

Chemistry databases

ChEMBLiCHEMBL2321640

Polymorphism and mutation databases

BioMutaiFXN

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transit peptidei1 – 41MitochondrionAdd BLAST41
ChainiPRO_000001012942 – 210Frataxin intermediate formAdd BLAST169
ChainiPRO_000001013056 – 210Frataxin(56-210)Add BLAST155
ChainiPRO_000039938878 – 210Frataxin(78-210)Add BLAST133
ChainiPRO_000028933181 – 210Frataxin mature formAdd BLAST130

Post-translational modificationi

Processed in two steps by mitochondrial processing peptidase (MPP). MPP first cleaves the precursor to intermediate form and subsequently converts the intermediate to yield frataxin mature form (frataxin(81-210)) which is the predominant form. The additional forms, frataxin(56-210) and frataxin(78-210), seem to be produced when the normal maturation process is impaired; their physiological relevance is unsure.5 Publications

Proteomic databases

EPDiQ16595
MaxQBiQ16595
PaxDbiQ16595
PeptideAtlasiQ16595
PRIDEiQ16595
TopDownProteomicsiQ16595-1 [Q16595-1]
Q16595-2 [Q16595-2]

2D gel databases

OGPiQ16595

PTM databases

iPTMnetiQ16595
PhosphoSitePlusiQ16595

Expressioni

Tissue specificityi

Expressed in the heart, peripheral blood lymphocytes and dermal fibroblasts.1 Publication

Gene expression databases

BgeeiENSG00000165060
CleanExiHS_FXN
ExpressionAtlasiQ16595 baseline and differential
GenevisibleiQ16595 HS

Organism-specific databases

HPAiCAB022164
HPA068304

Interactioni

Subunit structurei

Monomer (probable predominant form). Oligomer. Monomers and polymeric aggregates of >1 MDa have been isolated from mitochondria. A small fraction of heterologous overexpressed recombinant frataxin forms high-molecular wight aggregates that incoroprate iron (PubMed:11823441, PubMed:12755598, PubMed:15641778, PubMed:15581888). Interacts with LYRM4 (PubMed:17331979). Interacts with ACO1 (PubMed:20053667). Interacts with ISCU isoform 1 and isoform 2 (PubMed:12785837, PubMed:16091420). Interacts with FECH; one iron-bound FXN monomer seems to interact with a FECH homodimer (PubMed:15123683). Interacts with SDHA and SDHB (PubMed:15961414). Interacts with ACO2; the interaction is dependent on citrate (By similarity). Interacts with HSPA9 (PubMed:17331979, PubMed:26702583).By similarity11 Publications

Protein-protein interaction databases

BioGridi1086775 interactors.
CORUMiQ16595
IntActiQ16595 6 interactors.
MINTiQ16595
STRINGi9606.ENSP00000366482

Structurei

Secondary structure

1210
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi92 – 114Combined sources23
Beta strandi124 – 128Combined sources5
Beta strandi131 – 135Combined sources5
Turni138 – 140Combined sources3
Beta strandi142 – 148Combined sources7
Turni149 – 152Combined sources4
Beta strandi153 – 157Combined sources5
Beta strandi159 – 161Combined sources3
Beta strandi164 – 168Combined sources5
Beta strandi170 – 175Combined sources6
Turni176 – 178Combined sources3
Helixi182 – 194Combined sources13
Beta strandi206 – 208Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1EKGX-ray1.80A86-210[»]
1LY7NMR-A91-210[»]
3S4MX-ray1.30A82-210[»]
3S5DX-ray1.50A82-210[»]
3S5EX-ray1.31A82-210[»]
3S5FX-ray1.50A/B82-210[»]
3T3JX-ray1.70A82-210[»]
3T3KX-ray1.24A82-210[»]
3T3LX-ray1.15A82-210[»]
3T3TX-ray1.38A/B/C/D82-210[»]
3T3XX-ray1.57A/B82-210[»]
5KZ5electron microscopy14.30A/B/C/D/E/F/G/H/I/J/K/L42-210[»]
DisProtiDP00607
ProteinModelPortaliQ16595
SMRiQ16595
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ16595

Family & Domainsi

Sequence similaritiesi

Belongs to the frataxin family.Curated

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG3413 Eukaryota
COG1965 LUCA
GeneTreeiENSGT00390000005811
HOGENOMiHOG000190729
HOVERGENiHBG005745
InParanoidiQ16595
KOiK19054
OMAiQSVYLMN
OrthoDBiEOG091G0UR5
PhylomeDBiQ16595
TreeFamiTF318958

Family and domain databases

Gene3Di3.30.920.101 hit
InterProiView protein in InterPro
IPR017789 Frataxin
IPR002908 Frataxin/CyaY
IPR036524 Frataxin/CyaY_sf
IPR020895 Frataxin_CS
PANTHERiPTHR16821 PTHR16821, 1 hit
PfamiView protein in Pfam
PF01491 Frataxin_Cyay, 1 hit
PRINTSiPR00904 FRATAXIN
SMARTiView protein in SMART
SM01219 Frataxin_Cyay, 1 hit
TIGRFAMsiTIGR03421 FeS_CyaY, 1 hit
TIGR03422 mito_frataxin, 1 hit
PROSITEiView protein in PROSITE
PS01344 FRATAXIN_1, 1 hit
PS50810 FRATAXIN_2, 1 hit

Sequences (3)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q16595-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MWTLGRRAVA GLLASPSPAQ AQTLTRVPRP AELAPLCGRR GLRTDIDATC
60 70 80 90 100
TPRRASSNQR GLNQIWNVKK QSVYLMNLRK SGTLGHPGSL DETTYERLAE
110 120 130 140 150
ETLDSLAEFF EDLADKPYTF EDYDVSFGSG VLTVKLGGDL GTYVINKQTP
160 170 180 190 200
NKQIWLSSPS SGPKRYDWTG KNWVYSHDGV SLHELLAAEL TKALKTKLDL
210
SSLAYSGKDA
Length:210
Mass (Da):23,135
Last modified:July 15, 1999 - v2
Checksum:iECC81738779308CF
GO
Isoform 2 (identifier: Q16595-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     161-210: SGPKRYDWTGKNWVYSHDGVSLHELLAAELTKALKTKLDLSSLAYSGKDA → RLTWLLWLFHP

Note: Not highly expressed and may be artifactual.
Show »
Length:171
Mass (Da):19,095
Checksum:i54BDD6A74B2D22C9
GO
Isoform 3 (identifier: Q16595-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     161-210: SGPKRYDWTG...SSLAYSGKDA → RYVVDLSVMT...SCWPQSSLKP

Note: No experimental confirmation available. Gene prediction based on EST data.
Show »
Length:196
Mass (Da):21,416
Checksum:i306DDDE81A26C788
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti175Y → F in AAA98508 (PubMed:8596916).Curated1
Sequence conflicti175Y → F in AAA98510 (PubMed:8596916).Curated1
Sequence conflicti202S → W in AAA98508 (PubMed:8596916).Curated1
Sequence conflicti202S → W in AAA98510 (PubMed:8596916).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_016065106L → S in FRDA. 1 PublicationCorresponds to variant dbSNP:rs104894105Ensembl.1
Natural variantiVAR_002428122D → Y in FRDA. 3 PublicationsCorresponds to variant dbSNP:rs142157346Ensembl.1
Natural variantiVAR_002429130G → V in FRDA. 3 PublicationsCorresponds to variant dbSNP:rs104894107Ensembl.1
Natural variantiVAR_002430154I → F in FRDA; reduces interaction with LYRM4; the interaction is rescued by nickel; a murine cellular FRDA model, deleted for endogenous frataxin and expressing human mutant frataxin cDNA shows defects in mitochondrial structure, mitochondrial iron deposits, decreased enzymatic activity of some mitochondrial and cytoplasmic iron-sulfur cluster-containing enzymes, increased RNA-binding activity of ACO1 and increased sensitivity to oxidative stress. 4 PublicationsCorresponds to variant dbSNP:rs104894106Ensembl.1
Natural variantiVAR_002431155W → R in FRDA; reduces interaction with LYRM4; the interaction is rescued by nickel. 2 PublicationsCorresponds to variant dbSNP:rs138471431Ensembl.1
Natural variantiVAR_008139165R → C in FRDA; mild form. 1 PublicationCorresponds to variant dbSNP:rs138034837Ensembl.1
Natural variantiVAR_008140182L → F in FRDA. 1 PublicationCorresponds to variant dbSNP:rs139616452Ensembl.1
Natural variantiVAR_016066198L → R in FRDA. 1 PublicationCorresponds to variant dbSNP:rs144104124Ensembl.1
Natural variantiVAR_049100202S → C. Corresponds to variant dbSNP:rs1052195Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_001576161 – 210SGPKR…SGKDA → RLTWLLWLFHP in isoform 2. 1 PublicationAdd BLAST50
Alternative sequenceiVSP_047282161 – 210SGPKR…SGKDA → RYVVDLSVMTGLGKTGCTPT TACPSMSCWPQSSLKP in isoform 3. CuratedAdd BLAST50

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U43747 mRNA Translation: AAA98510.1
U43752
, U43748, U43749, U43750, U43751 Genomic DNA Translation: AAA98508.1
U43753
, U43748, U43749, U43750, U43751 Genomic DNA Translation: AAA98509.1
AL162730 Genomic DNA No translation available.
BC023633 mRNA Translation: AAH23633.1
BC048097 mRNA Translation: AAH48097.1
Y13751 Genomic DNA Translation: CAA74077.1
AF028240 Genomic DNA Translation: AAB84047.1
U93173 Genomic DNA Translation: AAD00734.1
CCDSiCCDS43834.1 [Q16595-3]
CCDS6626.1 [Q16595-1]
RefSeqiNP_000135.2, NM_000144.4 [Q16595-1]
NP_001155178.1, NM_001161706.1
NP_852090.1, NM_181425.2 [Q16595-3]
UniGeneiHs.20685

Genome annotation databases

EnsembliENST00000377270; ENSP00000366482; ENSG00000165060 [Q16595-1]
ENST00000396364; ENSP00000379650; ENSG00000165060 [Q16595-2]
ENST00000396366; ENSP00000379652; ENSG00000165060 [Q16595-3]
GeneIDi2395
KEGGihsa:2395
UCSCiuc004agz.3 human [Q16595-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism, Triplet repeat expansion

Similar proteinsi

Entry informationi

Entry nameiFRDA_HUMAN
AccessioniPrimary (citable) accession number: Q16595
Secondary accession number(s): A8MXJ6
, C9JJ89, O15545, O95656, Q15294, Q5VZ01
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1999
Last sequence update: July 15, 1999
Last modified: April 25, 2018
This is version 188 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome