Reviewed, UniProtKB/Swiss-Prot Q16595 (FRDA_HUMAN)

Names and origin

Protein names

Recommended name:
    Frataxin, mitochondrial
Alternative name(s):
    Friedreich ataxia protein
      Short name=Fxn
Cleaved into the following 3 chains:
    1- Recommended name:
            Frataxin intermediate form
    2- Recommended name:
            Frataxin(56-210)
    3- Recommended name:
            Frataxin(81-210)

Gene names

Name:	FXN
Synonyms:	FRDA, X25

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	210 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Probably involved in iron homeostasis. Anti-apoptotic protein which prevents mitochondrial damage and reactive oxygen species (ROS) production. Ref.13
Subunit structure	Monomer. Interacts with LYRM4 AND HSPA9. Ref.14
Subcellular location	Mitochondrion. Note: Mitochondrial and extramitochondrial. Ref.13 Ref.8 Ref.9
Tissue specificity	Frataxin(81-210) is expressed in the heart, peripheral blood lymphocytes and dermal fibroblasts. Ref.4
Post-translational modification	Processed in two steps by mitochondrial processing peptidase (MPP). MPP first cleaves the precursor to intermediate form and subsequently converts the intermediate to mature size protein. Two forms exist, frataxin(56-210) and frataxin(81-210) which is the main form of mature frataxin.
Involvement in disease	Defects in FXN are the cause of Friedreich ataxia (FA) [MIM:229300]. FA is an autosomal 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, FA 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. Ref.6 Ref.7 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.23
Sequence similarities	Belongs to the frataxin family.

Ontologies

Keywords
Cellular component	Mitochondrion
Coding sequence diversity	Alternative splicing Polymorphism Triplet repeat expansion
Disease	Disease mutation
Domain	Transit peptide
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	cellular iron ion homeostasis Inferred from mutant phenotype. Source: UniProtKB heme biosynthetic process Non-traceable author statement. Source: UniProtKB iron incorporation into metallo-sulfur cluster Inferred from direct assay. Source: UniProtKB positive regulation of cell growth Inferred from mutant phenotype. Source: UniProtKB positive regulation of cell proliferation Inferred from mutant phenotype. Source: UniProtKB positive regulation of lyase activity Inferred from mutant phenotype. Source: UniProtKB positive regulation of metalloenzyme activity Inferred from mutant phenotype. Source: UniProtKB positive regulation of oxidoreductase activity Inferred from mutant phenotype. Source: UniProtKB positive regulation of transferase activity Inferred from mutant phenotype. Source: UniProtKB protein autoprocessing Inferred from direct assay. Source: UniProtKB regulation of ferrochelatase activity Inferred from direct assay. Source: UniProtKB response to iron ion Inferred from mutant phenotype. Source: UniProtKB
Cellular component	cytosol Ref.4 Inferred from direct assay. Source: UniProtKB mitochondrial matrix Non-traceable author statement. Source: UniProtKB
Molecular function	2 iron, 2 sulfur cluster binding Inferred from direct assay. Source: UniProtKB ferric iron binding Inferred from direct assay. Source: UniProtKB ferrous iron binding Inferred from direct assay. Source: UniProtKB iron chaperone activity Inferred from direct assay. Source: UniProtKB protein binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q16595-1)

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.

Isoform 2 (identifier: Q16595-2)

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

Note: Not highly expressed and may be artifactual.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 41

41

Mitochondrion

Chain

42 – 210

169

Frataxin intermediate form

PRO_0000010129

Chain

56 – 210

155

Frataxin(56-210)

PRO_0000010130

Chain

81 – 210

130

Frataxin(81-210)

PRO_0000289331

Natural variations

Alternative sequence

161 – 210

50

SGPKR…SGKDA → RLTWLLWLFHP in isoform 2.

VSP_001576

Natural variant

106

1

L → S in FA. Ref.19

VAR_016065

Natural variant

122

1

D → Y in FA. Ref.6 Ref.7 Ref.21

VAR_002428

Natural variant

130

1

G → V in FA. Ref.18 Ref.20 Ref.21

VAR_002429

Natural variant

154

1

I → F in FA; reduces interaction with LYRM4. Interaction is rescued by nickel. Ref.14 Ref.18 Ref.1

VAR_002430

Natural variant

155

1

W → R in FA; reduces interaction with LYRM4. Interaction is rescued by nickel. Ref.14 Ref.22

VAR_002431

Natural variant

165

1

R → C in FA; mild form. Ref.20

VAR_008139

Natural variant

182

1

L → F in FA. Ref.20

VAR_008140

Natural variant

198

1

L → R in FA. Ref.23

VAR_016066

Natural variant

202

1

S → C: dbSNP rs1052195.

VAR_049100

Experimental info

Mutagenesis

53

1

R → G: Abolished cleavage of frataxin(81-210); when associated with G-54. Ref.4

Mutagenesis

54

1

R → G: Abolished cleavage of frataxin(81-210) and allows the accumulation of frataxin(56-210); when associated with G-53. Ref.4

Mutagenesis

79

1

R → G: Abolished cleavage of frataxin(81-210) and allows the accumulation of frataxin(56-210); when associated with G-80. Ref.4

Mutagenesis

80

1

K → G: Abolished cleavage of frataxin(81-210); when associated with G-79. Ref.4

Sequence conflict

175

1

Y → F in AAA98508. Ref.1

Sequence conflict

175

1

Y → F in AAA98510. Ref.1

Sequence conflict

202

1

S → W in AAA98508. Ref.1

Sequence conflict

202

1

S → W in AAA98510. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

210

Helix Strand Turn

Details...

Helix

92 – 113

22

Beta strand

124 – 128

5

Beta strand

131 – 135

5

Beta strand

142 – 148

7

Turn

149 – 152

4

Beta strand

153 – 158

6

Turn

159 – 161

3

Beta strand

162 – 168

7

Beta strand

170 – 175

6

Turn

176 – 178

3

Helix

182 – 194

13

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified July 15, 1999. Version 2. Checksum: ECC81738779308CF	FASTA	210	23,135
	10 20 30 40 50 60 MWTLGRRAVA GLLASPSPAQ AQTLTRVPRP AELAPLCGRR GLRTDIDATC TPRRASSNQR 70 80 90 100 110 120 GLNQIWNVKK QSVYLMNLRK SGTLGHPGSL DETTYERLAE ETLDSLAEFF EDLADKPYTF 130 140 150 160 170 180 EDYDVSFGSG VLTVKLGGDL GTYVINKQTP NKQIWLSSPS SGPKRYDWTG KNWVYSHDGV 190 200 210 SLHELLAAEL TKALKTKLDL SSLAYSGKDA
	Isoform 2. Checksum: 54BDD6A74B2D22C9	FASTA	171	19,095
	10 20 30 40 50 60 MWTLGRRAVA GLLASPSPAQ AQTLTRVPRP AELAPLCGRR GLRTDIDATC TPRRASSNQR 70 80 90 100 110 120 GLNQIWNVKK QSVYLMNLRK SGTLGHPGSL DETTYERLAE ETLDSLAEFF EDLADKPYTF 130 140 150 160 170 EDYDVSFGSG VLTVKLGGDL GTYVINKQTP NKQIWLSSPS RLTWLLWLFH P

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion." Campuzano V., Montermini L., Molto M.D., Pianese L., Cossee M., Cavalcanti F., Monros E., Rodius F., Duclos F., Monticelli A., Zara F., Canizares J., Koutnikova H., Bidichandani S., Gellera C., Brice A., Trouillas P., de Michele G. , Filla A., de Frutos R., Palau F., Patel P.I., di Donato S., Mandel J.-L., Cocozza S., Koenig M., Pandolfo M. Science 271:1423-1427(1996) [PubMed: 8596916] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], ALTERNATIVE SPLICING, VARIANT PHE-154.
[2]	"DNA sequence and analysis of human chromosome 9." Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., Bagguley C.L. , Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J., Dunham I. Nature 429:369-374(2004) [PubMed: 15164053] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Brain and Eye.
[4]	"In vivo maturation of human frataxin." Condo I., Ventura N., Malisan F., Rufini A., Tomassini B., Testi R. Hum. Mol. Genet. 16:1534-1540(2007) [PubMed: 17468497] [Abstract] Cited for: PROTEIN SEQUENCE OF 81-86, PROTEOLYTIC PROCESSING, MUTAGENESIS OF ARG-53; ARG-54; ARG-79 AND LYS-80, TISSUE SPECIFICITY.
[5]	"Correct sequence in exon 5a of x25: human frataxin (FRDA), F175(TTC)-->Y175(TAC) and W202(TGG)-->S202(TCC)." Laccone F., Schloesser M. Submitted (MAR-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 162-210.
[6]	"A novel splice site mutation (384+1G-A) in the Friedreich's ataxia gene." Doudney J.D., Pook M.A., Al-Mahdawi S., Carvajal J.J., Hillerman R., Chamberlain S. Submitted (NOV-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 89-128, VARIANT FA TYR-122.
[7]	Kostrzewa M. Submitted (JUN-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 89-128, VARIANT FA TYR-122.
[8]	"Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes." Campuzano V., Montermini L., Lutz Y., Cova L., Hindelang C., Jiralerspong S., Trottier Y., Kish S.J., Faucheux B., Trouillas P., Authier F.J., Duerr A., Mandel J.-L., Vescovi A., Pandolfo M., Koenig M. Hum. Mol. Genet. 6:1771-1780(1997) [PubMed: 9302253] [Abstract] Cited for: SUBCELLULAR LOCATION.
[9]	"Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin." Koutnikova H., Campuzano V., Foury F., Dolle P., Cazzalini O., Koenig M. Nat. Genet. 16:345-351(1997) [PubMed: 9241270] [Abstract] Cited for: SUBCELLULAR LOCATION.
[10]	"Maturation of frataxin within mammalian and yeast mitochondria: one-step processing by matrix processing peptidase." Gordon D.M., Shi Q., Dancis A., Pain D. Hum. Mol. Genet. 8:2255-2262(1999) [PubMed: 10545606] [Abstract] Cited for: PROTEOLYTIC PROCESSING.
[11]	"Yeast and human frataxin are processed to mature form in two sequential steps by the mitochondrial processing peptidase." Branda S.S., Cavadini P., Adamec J., Kalousek F., Taroni F., Isaya G. J. Biol. Chem. 274:22763-22769(1999) [PubMed: 10428860] [Abstract] Cited for: PROTEOLYTIC PROCESSING.
[12]	"Two-step processing of human frataxin by mitochondrial processing peptidase. Precursor and intermediate forms are cleaved at different rates." Cavadini P., Adamec J., Taroni F., Gakh O., Isaya G. J. Biol. Chem. 275:41469-41475(2000) [PubMed: 11020385] [Abstract] Cited for: PROTEOLYTIC PROCESSING.
[13]	"A pool of extramitochondrial frataxin that promotes cell survival." Condo I., Ventura N., Malisan F., Tomassini B., Testi R. J. Biol. Chem. 281:16750-16756(2006) [PubMed: 16608849] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[14]	"Mitochondrial frataxin interacts with ISD11 of the NFS1/ISCU complex and multiple mitochondrial chaperones." Shan Y., Napoli E., Cortopassi G. Hum. Mol. Genet. 16:929-941(2007) [PubMed: 17331979] [Abstract] Cited for: INTERACTION WITH LYRM4 AND HSPA9, CHARACTERIZATION OF VARIANTS PHE-154 AND ARG-155.
[15]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[16]	"Crystal structure of human frataxin." Dhe-Paganon S., Shigeta R., Chi Y.-I., Ristow M., Shoelson S.E. J. Biol. Chem. 275:30753-30756(2000) [PubMed: 10900192] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 88-210.
[17]	"Towards a structural understanding of Friedreich's ataxia: the solution structure of frataxin." Musco G., Stier G., Kolmerer B., Adinolfi S., Martin S., Frenkiel T., Gibson T., Pastore A. Structure 8:695-707(2000) [PubMed: 10903947] [Abstract] Cited for: STRUCTURE BY NMR OF 91-210.
[18]	"Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion." Bidichandani S.I., Ashizawa T., Patel P.I. Am. J. Hum. Genet. 60:1251-1256(1997) [PubMed: 9150176] [Abstract] Cited for: VARIANTS FA VAL-130 AND PHE-154.
[19]	"Identification of a missense mutation in a Friedreich's ataxia patient: implications for diagnosis and carrier studies." Bartolo C., Mendell J.R., Prior T.W. Am. J. Med. Genet. 79:396-399(1998) [PubMed: 9779809] [Abstract] Cited for: VARIANT FA SER-106.
[20]	"The correlation of clinical phenotype in Friedreich ataxia with the site of point mutations in the FRDA gene." Forrest S.M., Knight M., Delatycki M.B., Paris D., Williamson R., King J., Yeung L., Nassif N., Nicholson G.A. Neurogenetics 1:253-257(1998) [PubMed: 10732799] [Abstract] Cited for: VARIANTS FA VAL-130; CYS-165 AND PHE-182.
[21]	"Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes." Cossee M., Duerr A., Schmitt M., Dahl N., Trouillas P., Allinson P., Kostrzewa M., Nivelon-Chevallier A., Gustavson K.-H., Kohlschuetter A., Mueller U., Mandel J.-L., Brice A., Koenig M., Cavalcanti F., Tammaro A., de Michele G., Filla A. , Cocozza S., Labuda M., Montermini L., Poirier J., Pandolfo M. Ann. Neurol. 45:200-206(1999) [PubMed: 9989622] [Abstract] Cited for: VARIANTS FA TYR-122 AND VAL-130.
[22]	"A missense mutation (W155R) in an American patient with Friedreich's ataxia." Labuda M., Poirier J., Pandolfo M. Hum. Mutat. 13:506-506(1999) Cited for: VARIANT FA ARG-155.
[23]	"A novel missense mutation (L198R) in the Friedreich's ataxia gene." Al-Mahdawi S., Pook M., Chamberlain S. Hum. Mutat. 16:95-95(2000) [PubMed: 10874325] [Abstract] Cited for: VARIANT FA ARG-198.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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. Translation: CAH71829.1.
BC023633 mRNA. Translation: AAH23633.1.
BC048097 mRNA. Translation: AAH48097.1.
U93173 Genomic DNA. Translation: AAD00734.1.
AF028240 Genomic DNA. Translation: AAB84047.1.
Y13751 Genomic DNA. Translation: CAA74077.1.

IPI

IPI00217745.
IPI00293425.

RefSeq

NP_000135.2.
NP_001155178.1.
NP_852090.1.

UniGene

Hs.20685

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1EKG	X-ray	1.80	A	88-210	[»]
1LY7	NMR	-	A	91-210	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

Q16595. 2 interactions.

STRING

Q16595.

Protein family/group databases

TCDB

9.B.21.1.1. frataxin family.

2-D gel databases

OGP

Q16595.

Proteomic databases

PeptideAtlas

Q16595.

PRIDE

Q16595.

Genome annotation databases

Ensembl

ENST00000377270; ENSP00000366482; ENSG00000165060; Homo sapiens. [Genome view]

GeneID

2395.

KEGG

hsa:2395.

NMPDR

fig|9606.3.peg.31391.

UCSC

uc004aha.1. human.

Organism-specific databases

CTD

2395.

GeneCards

GC09P070840.

H-InvDB

HIX0025740.

HGNC

HGNC:3951. FXN.

HPA

CAB022164.

MIM

229300. phenotype.
606829. gene.

Orphanet

95. Friedreich ataxia.

PharmGKB

PA28369.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG11242.

HOGENOM

HBG125781.

HOVERGEN

Q16595.

InParanoid

Q16595.

OMA

DETAYER.

OrthoDB

EOG9C5G4B.

PhylomeDB

Q16595.

Gene expression databases

ArrayExpress

Q16595.

Bgee

Q16595.

CleanEx

HS_FXN.

Genevestigator

Q16595.

GermOnline

ENSG00000165060. Homo sapiens.

Family and domain databases

InterPro

IPR017789. Frataxin.
IPR002908. Frataxin-like.
IPR020895. Frataxin_CS.
IPR001794. Frataxin_sub.
[Graphical view]

Gene3D

G3DSA:3.30.920.10. Frataxin_like. 1 hit.

Pfam

PF01491. Frataxin_Cyay. 1 hit.
[Graphical view]

PRINTS

PR00904. FRATAXIN.

TIGRFAMs

TIGR03421. FeS_CyaY. 1 hit.
TIGR03422. mito_frataxin. 1 hit.

PROSITE

PS01344. FRATAXIN_1. 1 hit.
PS50810. FRATAXIN_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

9641.

SOURCE

Search...

Entry information

Entry name

FRDA_HUMAN

Accession

Primary (citable) accession number: Q16595
Secondary accession number(s): O15545 , O95656, Q15294, Q5VZ01

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1999
Last sequence update:	July 15, 1999
Last modified:	February 9, 2010
This is version 110 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.