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Q9NS18 (GLRX2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 118. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Glutaredoxin-2, mitochondrial
Gene names
Name:GLRX2
Synonyms:GRX2
ORF Names:CGI-133
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length164 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Glutathione-dependent oxidoreductase that facilitates the maintenance of mitochondrial redox homeostasis upon induction of apoptosis by oxidative stress. Involved in response to hydrogen peroxide and regulation of apoptosis caused by oxidative stress. Acts as a very efficient catalyst of monothiol reactions because of its high affinity for protein glutathione-mixed disulfides. Can receive electrons not only from glutathione (GSH), but also from thioredoxin reductase supporting both monothiol and dithiol reactions. Efficiently catalyzes both glutathionylation and deglutathionylation of mitochondrial complex I, which in turn regulates the superoxide production by the complex. Overexpression decreases the susceptibility to apoptosis and prevents loss of cardiolipin and cytochrome c release. Ref.1 Ref.9 Ref.10 Ref.11

Enzyme regulation

The 2Fe-2S present in the homodimer leads to inactivation of the enzyme. The 2Fe-2S may serve as a redox sensor: the presence of one-electron oxidants or reductants leading to the loss of the 2Fe-2S cluster, subsequent monomerization and activation of the enzyme. Unlike other glutaredoxins, it is not inhibited by oxidation of structural Cys residues. Ref.12

Subunit structure

Monomer; active form. Homodimer; inactive form. The homodimer is probably linked by 1 2Fe-2S cluster. Ref.12

Subcellular location

Isoform 1: Mitochondrion Ref.1.

Isoform 2: Nucleus Ref.1.

Tissue specificity

Widely expressed. Expressed in brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta and lung. Not expressed in peripheral blood leukocytes. Ref.1 Ref.7 Ref.8

Miscellaneous

The absence of GLRX2 dramatically sensitizes cells to cell death induced by doxorubicin/adriamycin and phenylarsine oxide.

Sequence similarities

Belongs to the glutaredoxin family.

Contains 1 glutaredoxin domain.

Biophysicochemical properties

Kinetic parameters:

KM=5.9 mM for GSH Ref.9

KM=0.77 mM for glutathionylated ribonuclease A

KM=4.3 mM for glutathionylated BSA

KM=0.11 mM for glutathionylated beta-mercaptoethanol

Sequence caution

The sequence AAD34128.1 differs from that shown. Reason: Frameshift at several positions.

The sequence AAH28113.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
   Biological processElectron transport
Transport
   Cellular componentMitochondrion
Nucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainRedox-active center
Transit peptide
   Ligand2Fe-2S
Iron
Iron-sulfur
Metal-binding
   PTMDisulfide bond
Glutathionylation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processDNA protection

Non-traceable author statement Ref.1Ref.2. Source: UniProtKB

apoptotic process

Non-traceable author statement Ref.1. Source: UniProtKB

cell differentiation

Non-traceable author statement Ref.1. Source: UniProtKB

cell redox homeostasis

Traceable author statement Ref.2. Source: UniProtKB

glutathione metabolic process

Traceable author statement Ref.2. Source: UniProtKB

protein folding

Traceable author statement Ref.1Ref.2. Source: GOC

regulation of signal transduction

Non-traceable author statement Ref.1. Source: UniProtKB

regulation of transcription, DNA-templated

Non-traceable author statement Ref.1. Source: UniProtKB

response to hydrogen peroxide

Inferred from direct assay Ref.2. Source: UniProtKB

response to organic substance

Inferred from direct assay Ref.2. Source: UniProtKB

response to redox state

Traceable author statement Ref.1. Source: UniProtKB

response to temperature stimulus

Non-traceable author statement Ref.2. Source: UniProtKB

   Cellular_componentmitochondrion

Inferred from direct assay Ref.1Ref.2. Source: UniProtKB

nucleus

Inferred from direct assay Ref.1. Source: UniProtKB

   Molecular_function2 iron, 2 sulfur cluster binding

Inferred from electronic annotation. Source: UniProtKB-KW

arsenate reductase (glutaredoxin) activity

Traceable author statement Ref.1Ref.2. Source: UniProtKB

electron carrier activity

Non-traceable author statement Ref.1. Source: UniProtKB

glutathione disulfide oxidoreductase activity

Traceable author statement Ref.1Ref.2. Source: UniProtKB

metal ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

protein disulfide isomerase activity

Traceable author statement Ref.1Ref.2. Source: UniProtKB

protein disulfide oxidoreductase activity

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q9NS18-1)

Also known as: Grx2a;

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: Q9NS18-2)

Also known as: Grx2b;

The sequence of this isoform differs from the canonical sequence as follows:
     1-40: MIWRRAALAG...AGAAAAAASG → MNPRDKQVSR...PGRTRSAARR

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 1919Mitochondrion Potential
Chain20 – 164145Glutaredoxin-2, mitochondrial
PRO_0000011628

Regions

Domain57 – 157101Glutaredoxin

Sites

Metal binding681Iron-sulfur (2Fe-2S); shared with dimeric partner; in inactive form Probable
Metal binding1531Iron-sulfur (2Fe-2S); shared with dimeric partner; in inactive form Probable
Binding site741Glutathione
Binding site1091Glutathione
Binding site1211Glutathione; via amide nitrogen and carbonyl oxygen

Amino acid modifications

Modified residue771S-glutathionyl cysteine; alternate
Disulfide bond77 ↔ 80Redox-active; alternate By similarity

Natural variations

Alternative sequence1 – 4040MIWRR…AAASG → MNPRDKQVSRFSPLKDVYTW VALAGIQRSGSPGRTRSAAR R in isoform 2.
VSP_015221
Natural variant951K → E. Ref.3
Corresponds to variant rs34237236 [ dbSNP | Ensembl ].
VAR_025234
Isoform 2:
Natural variant401R → W.

Experimental info

Mutagenesis681C → S: Abolishes absorption at 320 nm and 420 nm suggesting the loss of 2Fe-2S-binding. Ref.12
Mutagenesis781S → P: Specifically increases the specific activity but decreases affinity for glutathionylated substrates. Ref.9
Mutagenesis801C → S: Strongly impairs enzymatic activity. Ref.9
Mutagenesis1531C → S: Abolishes absorption at 320 nm and 420 nm suggesting the loss of 2Fe-2S-binding. Ref.12

Secondary structure

..................... 164
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (Grx2a) [UniParc].

Last modified October 1, 2000. Version 1.
Checksum: D9798A01BB532A5D

FASTA16418,052
        10         20         30         40         50         60 
MIWRRAALAG TRLVWSRSGS AGWLDRAAGA AGAAAAAASG MESNTSSSLE NLATAPVNQI 

        70         80         90        100        110        120 
QETISDNCVV IFSKTSCSYC TMAKKLFHDM NVNYKVVELD LLEYGNQFQD ALYKMTGERT 

       130        140        150        160 
VPRIFVNGTF IGGATDTHRL HKEGKLLPLV HQCYLKKSKR KEFQ 

« Hide

Isoform 2 (Grx2b) [UniParc].

Checksum: D4A1F78015B516D4
Show »

FASTA16518,726

References

« Hide 'large scale' references
[1]"Cloning and expression of a novel human glutaredoxin (Grx2) with mitochondrial and nuclear isoforms."
Lundberg M., Johansson C., Chandra J., Enoksson M., Jacobsson G., Ljung J., Johansson M., Holmgren A.
J. Biol. Chem. 276:26269-26275(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
Tissue: Colon and Testis.
[2]"Identification and characterization of a new mammalian glutaredoxin (thioltransferase), Grx2."
Gladyshev V.N., Liu A., Novoselov S.V., Krysan K., Sun Q.-A., Kryukov V.M., Kryukov G.V., Lou M.F.
J. Biol. Chem. 276:30374-30380(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]NIEHS SNPs program
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT GLU-95.
[4]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]"Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics."
Lai C.-H., Chou C.-Y., Ch'ang L.-Y., Liu C.-S., Lin W.-C.
Genome Res. 10:703-713(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 4-164 (ISOFORM 1).
[6]"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] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 4-164 (ISOFORM 1).
Tissue: Mammary gland.
[7]"Cellular and plasma levels of human glutaredoxin 1 and 2 detected by sensitive ELISA systems."
Lundberg M., Fernandes A.P., Kumar S., Holmgren A.
Biochem. Biophys. Res. Commun. 319:801-809(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[8]"Expression of glutaredoxin is highly cell specific in human lung and is decreased by transforming growth factor-beta in vitro and in interstitial lung diseases in vivo."
Peltoniemi M., Kaarteenaho-Wiik R., Saily M., Sormunen R., Paakko P., Holmgren A., Soini Y., Kinnula V.L.
Hum. Pathol. 35:1000-1007(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
[9]"Human mitochondrial glutaredoxin reduces S-glutathionylated proteins with high affinity accepting electrons from either glutathione or thioredoxin reductase."
Johansson C., Lillig C.H., Holmgren A.
J. Biol. Chem. 279:7537-7543(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF SER-78 AND CYS-80.
[10]"Short interfering RNA-mediated silencing of glutaredoxin 2 increases the sensitivity of HeLa cells toward doxorubicin and phenylarsine oxide."
Lillig C.H., Loenn M.E., Enoksson M., Fernandes A.P., Holmgren A.
Proc. Natl. Acad. Sci. U.S.A. 101:13227-13232(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[11]"Overexpression of glutaredoxin 2 attenuates apoptosis by preventing cytochrome c release."
Enoksson M., Fernandes A.P., Prast S., Lillig C.H., Holmgren A., Orrenius S.
Biochem. Biophys. Res. Commun. 327:774-779(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[12]"Characterization of human glutaredoxin 2 as iron-sulfur protein: a possible role as redox sensor."
Lillig C.H., Berndt C., Vergnolle O., Loenn M.E., Hudemann C., Bill E., Holmgren A.
Proc. Natl. Acad. Sci. U.S.A. 102:8168-8173(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBUNIT, ENZYME REGULATION, METAL-BINDING, MUTAGENESIS OF CYS-68 AND CYS-153.
[13]"Solution structure of RSGI RUH-044, an N-terminal 2 domain of glutaredoxin 2 from human cDNA."
RIKEN structural genomics initiative (RSGI)
Submitted (NOV-2005) to the PDB data bank
Cited for: STRUCTURE BY NMR OF 48-164.
[14]"Reversible sequestration of active site cysteines in a 2Fe-2S-bridged dimer provides a mechanism for glutaredoxin 2 regulation in human mitochondria."
Johansson C., Kavanagh K.L., Gileadi O., Oppermann U.
J. Biol. Chem. 282:3077-3082(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) OF 50-164 IN COMPLEX WITH GLUTATHIONE.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF132495 mRNA. Translation: AAF37320.2.
AF290514 mRNA. Translation: AAK83089.1.
AY038988 mRNA. Translation: AAK72499.1.
DQ194815 Genomic DNA. Translation: ABA03170.1.
AL136370 Genomic DNA. Translation: CAI10820.1.
AL136370 Genomic DNA. Translation: CAI10821.1.
AF151891 mRNA. Translation: AAD34128.1. Frameshift.
BC028113 mRNA. Translation: AAH28113.1. Different initiation.
RefSeqNP_001230328.1. NM_001243399.1.
NP_057150.2. NM_016066.4.
NP_932066.1. NM_197962.2.
XP_005245288.1. XM_005245231.2.
UniGeneHs.458283.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2CQ9NMR-A48-164[»]
2FLSX-ray2.05A56-164[»]
2HT9X-ray1.90A/B41-164[»]
ProteinModelPortalQ9NS18.
SMRQ9NS18. Positions 54-164.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid119228. 2 interactions.
STRING9606.ENSP00000356410.

Chemistry

DrugBankDB00143. Glutathione.

PTM databases

PhosphoSiteQ9NS18.

Polymorphism databases

DMDM73919686.

Proteomic databases

PaxDbQ9NS18.
PRIDEQ9NS18.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000367439; ENSP00000356409; ENSG00000023572. [Q9NS18-1]
ENST00000367440; ENSP00000356410; ENSG00000023572. [Q9NS18-2]
GeneID51022.
KEGGhsa:51022.
UCSCuc001gsz.2. human. [Q9NS18-1]
uc001gta.2. human. [Q9NS18-2]

Organism-specific databases

CTD51022.
GeneCardsGC01M193065.
HGNCHGNC:16065. GLRX2.
HPAHPA023087.
MIM606820. gene.
neXtProtNX_Q9NS18.
PharmGKBPA28732.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0695.
HOGENOMHOG000095204.
HOVERGENHBG096801.
KOK03676.
OMAGMESNTS.
OrthoDBEOG7QRQWZ.
PhylomeDBQ9NS18.
TreeFamTF319627.

Enzyme and pathway databases

SABIO-RKQ9NS18.

Gene expression databases

BgeeQ9NS18.
CleanExHS_GLRX2.
GenevestigatorQ9NS18.

Family and domain databases

Gene3D3.40.30.10. 1 hit.
InterProIPR002109. Glutaredoxin.
IPR011899. Glutaredoxin_euk/vir.
IPR014025. Glutaredoxin_subgr.
IPR015450. Grx-2.
IPR012336. Thioredoxin-like_fold.
[Graphical view]
PANTHERPTHR10168:SF17. PTHR10168:SF17. 1 hit.
PfamPF00462. Glutaredoxin. 1 hit.
[Graphical view]
PRINTSPR00160. GLUTAREDOXIN.
SUPFAMSSF52833. SSF52833. 1 hit.
TIGRFAMsTIGR02180. GRX_euk. 1 hit.
PROSITEPS51354. GLUTAREDOXIN_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceQ9NS18.
GeneWikiGLRX2.
GenomeRNAi51022.
NextBio53548.
PROQ9NS18.
SOURCESearch...

Entry information

Entry nameGLRX2_HUMAN
AccessionPrimary (citable) accession number: Q9NS18
Secondary accession number(s): Q3LR69 expand/collapse secondary AC list , Q7L1N7, Q96JC0, Q9Y3D4
Entry history
Integrated into UniProtKB/Swiss-Prot: August 30, 2005
Last sequence update: October 1, 2000
Last modified: April 16, 2014
This is version 118 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM