Reviewed, UniProtKB/Swiss-Prot Q9NS18 (GLRX2_HUMAN)

Names and origin

Protein names

Recommended name:
    Glutaredoxin-2, mitochondrial

Gene names

Name:	GLRX2
Synonyms:	GRX2
ORF Names:	CGI-133

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	164 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	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 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.

Ontologies

Keywords
Biological process	Electron transport Transport
Cellular component	Mitochondrion Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Redox-active center Transit peptide
Ligand	2Fe-2S Iron Iron-sulfur Metal-binding
PTM	Disulfide bond Glutathionylation
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	DNA protection Ref.1 Ref.2 Non-traceable author statement. Source: UniProtKB apoptosis Ref.1 Non-traceable author statement. Source: UniProtKB cell differentiation Ref.1 Non-traceable author statement. Source: UniProtKB cell redox homeostasis Ref.2 Traceable author statement. Source: UniProtKB electron transport chain Inferred from electronic annotation. Source: UniProtKB-KW glutathione metabolic process Ref.2 Traceable author statement. Source: UniProtKB protein thiol-disulfide exchange Ref.1 Ref.2 Traceable author statement. Source: UniProtKB redox signal response Ref.1 Traceable author statement. Source: UniProtKB regulation of signal transduction Ref.1 Non-traceable author statement. Source: UniProtKB regulation of transcription Ref.1 Non-traceable author statement. Source: UniProtKB response to hydrogen peroxide Ref.2 Inferred from direct assay. Source: UniProtKB response to organic substance Ref.2 Inferred from direct assay. Source: UniProtKB response to temperature stimulus Ref.2 Non-traceable author statement. Source: UniProtKB transport Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	mitochondrion Ref.1 Ref.2 Inferred from direct assay. Source: UniProtKB nucleus Ref.1 Inferred from direct assay. Source: UniProtKB
Molecular function	2 iron, 2 sulfur cluster binding Inferred from electronic annotation. Source: UniProtKB-KW arsenate reductase (glutaredoxin) activity Ref.1 Ref.2 Traceable author statement. Source: UniProtKB electron carrier activity Ref.1 Non-traceable author statement. Source: UniProtKB glutathione disulfide oxidoreductase activity Ref.1 Ref.2 Traceable author statement. Source: UniProtKB iron ion binding Inferred from electronic annotation. Source: UniProtKB-KW 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

Note: Polymorphism in position 40: Arg->Trp.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Transit peptide

1 – 19

19

Mitochondrion Potential

Chain

20 – 164

145

Glutaredoxin-2, mitochondrial

PRO_0000011628

Regions

Domain

57 – 157

101

Glutaredoxin

Sites

Metal binding

68

1

Iron-sulfur (2Fe-2S); shared with dimeric partner; in inactive form Probable

Metal binding

153

1

Iron-sulfur (2Fe-2S); shared with dimeric partner; in inactive form Probable

Binding site

74

1

Glutathione

Binding site

109

1

Glutathione

Binding site

121

1

Glutathione; via amide nitrogen and carbonyl oxygen

Amino acid modifications

Modified residue

77

1

S-glutathionyl cysteine; alternate

Disulfide bond

77 ↔ 80

Redox-active; alternate By similarity

Natural variations

Alternative sequence

1 – 40

40

MIWRR…AAASG → MNPRDKQVSRFSPLKDVYTW VALAGIQRSGSPGRTRSAAR R in isoform 2.

VSP_015221

Natural variant

95

1

K → E Ref.3

VAR_025234

Experimental info

Mutagenesis

68

1

C → S: Abolishes absorption at 320 nm and 420 nm suggesting the loss of 2Fe-2S-binding. Ref.12

Mutagenesis

78

1

S → P: Specifically increases the specific activity but decreases affinity for glutathionylated substrates. Ref.9

Mutagenesis

80

1

C → S: Strongly impairs enzymatic activity. Ref.9

Mutagenesis

153

1

C → S: Abolishes absorption at 320 nm and 420 nm suggesting the loss of 2Fe-2S-binding. Ref.12

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

164

Helix Strand Turn

Details...

Helix

56 – 66

11

Beta strand

68 – 73

6

Helix

78 – 89

12

Beta strand

94 – 98

5

Helix

99 – 101

3

Helix

105 – 116

12

Beta strand

123 – 126

4

Beta strand

129 – 133

5

Helix

134 – 142

9

Helix

146 – 154

9

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (Grx2a) [UniParc]. Last modified October 1, 2000. Version 1. Checksum: D9798A01BB532A5D	FASTA	164	18,052
	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
	Isoform 2 (Grx2b). Checksum: D4A1F78015B516D4	FASTA	165	18,726
	10 20 30 40 50 60 MNPRDKQVSR FSPLKDVYTW VALAGIQRSG SPGRTRSAAR RMESNTSSSL ENLATAPVNQ 70 80 90 100 110 120 IQETISDNCV VIFSKTSCSY CTMAKKLFHD MNVNYKVVEL DLLEYGNQFQ DALYKMTGER 130 140 150 160 TVPRIFVNGT FIGGATDTHR LHKEGKLLPL VHQCYLKKSK RKEFQ

References

	« Hide 'large scale' referencesShow '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: 11297543] [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: 11397793] [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. , 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: 16710414] [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: 10810093] [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: 15489334] [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: 15184054] [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: 15297967] [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: 14676218] [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: 15328416] [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: 15649413] [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: 15917333] [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]	"Crystal structure of human glutaredoxin 2 complexed with glutathione." Structural genomics consortium (SGC) Submitted (JAN-2006) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.05 ANGSTROMS) OF 50-164 IN COMPLEX WITH GLUTATHIONE.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.

IPI

IPI00007045.
IPI00100044.

RefSeq

NP_057150.2.
NP_932066.1.

UniGene

Hs.458283

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2CQ9	NMR	-	A	48-164	[»]
2FLS	X-ray	2.05	A	56-164	[»]
2HT9	X-ray	1.90	A/B	41-164	[»]

ModBase

Search...

PTM databases

PhosphoSite

Q9NS18.

Proteomic databases

PRIDE

Q9NS18.

Genome annotation databases

Ensembl

ENSG00000023572. Homo sapiens. [Contig view]

GeneID

51022.

KEGG

hsa:51022.

UCSC

uc001gsz.1. human.
uc001gta.1. human.

Organism-specific databases

GeneCards

GC01M191332.

H-InvDB

HIX0001437.

HGNC

HGNC:16065. GLRX2.

MIM

606820. gene.

PharmGKB

PA28732.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

Q9NS18.

OMA

Q9NS18. ETISHNC.

Gene expression databases

ArrayExpress

Q9NS18.

Bgee

Q9NS18.

CleanEx

HS_GLRX2.

GermOnline

ENSG00000023572. Homo sapiens.

Family and domain databases

InterPro

IPR011767. GLR_AS.
IPR002109. Glutaredoxin.
IPR014025. Glutaredoxin_sub.
IPR015450. Grx-2.
IPR011899. GRX_euk.
IPR012335. Thioredoxin_fold.
[Graphical view]

Gene3D

G3DSA:3.40.30.10. Thioredoxin_fold. 1 hit.

PANTHER

PTHR10168:SF17. Grx-2. 1 hit.

Pfam

PF00462. Glutaredoxin. 1 hit.
[Graphical view]

PRINTS

PR00160. GLUTAREDOXIN.

TIGRFAMs

TIGR02180. GRX_euk. 1 hit.

PROSITE

PS00195. GLUTAREDOXIN_1. False negative.
PS51354. GLUTAREDOXIN_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB00143. Glutathione.

NextBio

53548.

SOURCE

Search...

Entry information

Entry name

GLRX2_HUMAN

Accession

Primary (citable) accession number: Q9NS18
Secondary accession number(s): Q3LR69 , Q7L1N7, Q96JC0, Q9Y3D4

Entry history

Integrated into UniProtKB/Swiss-Prot:	August 30, 2005
Last sequence update:	October 1, 2000
Last modified:	July 7, 2009
This is version 69 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)