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Protein

Phospholipid hydroperoxide glutathione peroxidase, mitochondrial

Gene

GPX4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Protects cells against membrane lipid peroxidation and cell death. Required for normal sperm development and male fertility. Could play a major role in protecting mammals from the toxicity of ingested lipid hydroperoxides. Essential for embryonic development. Protects from radiation and oxidative damage. Essential for maturation and survival of photoreceptor cells. Plays a role in a primary T cell response to viral and parasitic infection by protecting T cells from ferroptosis, a cell death resulting from an iron-dependent accumulation of lipid reactive oxygen species, and by supporting T cell expansion.By similarity

Catalytic activityi

2 glutathione + a hydroperoxy-fatty-acyl-[lipid] = glutathione disulfide + a hydroxy-fatty-acyl-[lipid] + H2O.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei731

GO - Molecular functioni

  • glutathione peroxidase activity Source: UniProtKB
  • phospholipid-hydroperoxide glutathione peroxidase activity Source: UniProtKB-EC

GO - Biological processi

  • lipoxygenase pathway Source: Reactome
  • multicellular organism development Source: UniProtKB-KW
  • oxidation-reduction process Source: UniProtKB
  • phospholipid metabolic process Source: UniProtKB
  • response to oxidative stress Source: InterPro
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Oxidoreductase, Peroxidase

Enzyme and pathway databases

BioCyciMetaCyc:HS09562-MONOMER.
ZFISH:HS09562-MONOMER.
BRENDAi1.11.1.12. 2681.
ReactomeiR-HSA-2142688. Synthesis of 5-eicosatetraenoic acids.
R-HSA-2142712. Synthesis of 12-eicosatetraenoic acid derivatives.
R-HSA-2142770. Synthesis of 15-eicosatetraenoic acid derivatives.
SABIO-RKP36969.

Protein family/group databases

MoonProtiP36969.
PeroxiBasei3603. HsGPx04-A.
3632. HsGPx04-B.
3633. HsGPx04-C.

Chemistry databases

SwissLipidsiSLP:000001633.

Names & Taxonomyi

Protein namesi
Recommended name:
Phospholipid hydroperoxide glutathione peroxidase, mitochondrial (EC:1.11.1.12)
Short name:
PHGPx
Alternative name(s):
Glutathione peroxidase 4
Short name:
GPx-4
Short name:
GSHPx-4
Gene namesi
Name:GPX4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

HGNCiHGNC:4556. GPX4.

Subcellular locationi

GO - Cellular componenti

  • cytosol Source: Reactome
  • extracellular exosome Source: UniProtKB
  • mitochondrion Source: UniProtKB
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Mitochondrion

Pathology & Biotechi

Involvement in diseasei

Spondylometaphyseal dysplasia, Sedaghatian type (SMDS)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of spondylometaphyseal dysplasia, a group of short stature disorders distinguished by abnormalities in the vertebrae and the metaphyses of the tubular bones. SMDS is a neonatal lethal form characterized by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, cardiac conduction defects, and central nervous system abnormalities.
See also OMIM:250220

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi73U → A: Loss of enzyme activity. 1 Publication1
Mutagenesisi73U → C: Almost complete loss of enzyme activity. 1 Publication1

Keywords - Diseasei

Dwarfism

Organism-specific databases

DisGeNETi2879.
MalaCardsiGPX4.
MIMi250220. phenotype.
OpenTargetsiENSG00000167468.
Orphaneti93317. Spondylometaphyseal dysplasia, Sedaghatian type.
PharmGKBiPA28952.

Chemistry databases

DrugBankiDB00143. Glutathione.

Polymorphism and mutation databases

BioMutaiGPX4.
DMDMi172045844.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_0000013067? – 197Phospholipid hydroperoxide glutathione peroxidase, mitochondrial
Transit peptidei1 – ?MitochondrionSequence analysis

Proteomic databases

EPDiP36969.
MaxQBiP36969.
PaxDbiP36969.
PeptideAtlasiP36969.
PRIDEiP36969.

2D gel databases

REPRODUCTION-2DPAGEIPI00304814.
UCD-2DPAGEP36969.

PTM databases

iPTMnetiP36969.
PhosphoSitePlusiP36969.
SwissPalmiP36969.

Expressioni

Tissue specificityi

Present primarily in testis.

Gene expression databases

BgeeiENSG00000167468.
CleanExiHS_GPX4.
ExpressionAtlasiP36969. baseline and differential.
GenevisibleiP36969. HS.

Organism-specific databases

HPAiCAB008630.
HPA058546.

Interactioni

Subunit structurei

Monomer. Has a tendency to form higher mass oligomers.1 Publication

Protein-protein interaction databases

BioGridi109137. 39 interactors.
IntActiP36969. 6 interactors.
STRINGi9606.ENSP00000346103.

Structurei

Secondary structure

1197
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi35 – 37Combined sources3
Helixi41 – 43Combined sources3
Beta strandi45 – 48Combined sources4
Beta strandi53 – 55Combined sources3
Helixi56 – 59Combined sources4
Beta strandi62 – 69Combined sources8
Beta strandi71 – 73Combined sources3
Helixi76 – 90Combined sources15
Helixi91 – 93Combined sources3
Beta strandi95 – 101Combined sources7
Turni104 – 107Combined sources4
Helixi113 – 121Combined sources9
Turni122 – 124Combined sources3
Beta strandi127 – 130Combined sources4
Beta strandi134 – 137Combined sources4
Helixi142 – 148Combined sources7
Turni151 – 153Combined sources3
Beta strandi156 – 160Combined sources5
Beta strandi167 – 170Combined sources4
Beta strandi176 – 180Combined sources5
Helixi187 – 190Combined sources4
Helixi194 – 196Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2GS3X-ray1.90A36-197[»]
2OBIX-ray1.55A29-197[»]
ProteinModelPortaliP36969.
SMRiP36969.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP36969.

Family & Domainsi

Sequence similaritiesi

Belongs to the glutathione peroxidase family.Curated

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG1651. Eukaryota.
COG0386. LUCA.
GeneTreeiENSGT00760000119230.
HOGENOMiHOG000277054.
HOVERGENiHBG004333.
InParanoidiP36969.
KOiK05361.
OMAiMSLGRLC.
PhylomeDBiP36969.
TreeFamiTF338735.

Family and domain databases

CDDicd00340. GSH_Peroxidase. 1 hit.
Gene3Di3.40.30.10. 1 hit.
InterProiIPR000889. Glutathione_peroxidase.
IPR029759. GPX_AS.
IPR029760. GPX_CS.
IPR012336. Thioredoxin-like_fold.
[Graphical view]
PANTHERiPTHR11592. PTHR11592. 1 hit.
PfamiPF00255. GSHPx. 1 hit.
[Graphical view]
PIRSFiPIRSF000303. Glutathion_perox. 1 hit.
SUPFAMiSSF52833. SSF52833. 1 hit.
PROSITEiPS00460. GLUTATHIONE_PEROXID_1. 1 hit.
PS00763. GLUTATHIONE_PEROXID_2. 1 hit.
PS51355. GLUTATHIONE_PEROXID_3. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative initiation. AlignAdd to basket

Isoform Mitochondrial (identifier: P36969-1) [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
MSLGRLCRLL KPALLCGALA APGLAGTMCA SRDDWRCARS MHEFSAKDID
60 70 80 90 100
GHMVNLDKYR GFVCIVTNVA SQUGKTEVNY TQLVDLHARY AECGLRILAF
110 120 130 140 150
PCNQFGKQEP GSNEEIKEFA AGYNVKFDMF SKICVNGDDA HPLWKWMKIQ
160 170 180 190
PKGKGILGNA IKWNFTKFLI DKNGCVVKRY GPMEEPLVIE KDLPHYF
Length:197
Mass (Da):22,175
Last modified:February 26, 2008 - v3
Checksum:i1AE3BC7AE42FDDB1
GO
Isoform Cytoplasmic (identifier: P36969-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-27: Missing.

Show »
Length:170
Mass (Da):19,525
Checksum:iB7FA0B3831DEF7DB
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0170632S → N.2 PublicationsCorresponds to variant rs8178967dbSNPEnsembl.1
Natural variantiVAR_017064120A → T in a patient affected by cryptorchidism. 1 PublicationCorresponds to variant rs76201145dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0187401 – 27Missing in isoform Cytoplasmic. CuratedAdd BLAST27

Non-standard residue

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Non-standard residuei73Selenocysteine1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X71973 mRNA. Translation: CAA50793.1.
AF060972 Genomic DNA. Translation: AAC32261.1.
AY324108 Genomic DNA. Translation: AAP72965.1.
AC004151 Genomic DNA. Translation: AAC03239.1.
AC005390 Genomic DNA. Translation: AAC28920.1.
BC011836 mRNA. Translation: AAH11836.1.
BC021567 mRNA. Translation: AAH21567.1.
BC022071 mRNA. Translation: AAH22071.1.
BC032695 mRNA. Translation: AAH32695.3.
BC039849 mRNA. Translation: AAH39849.1.
CCDSiCCDS42457.1. [P36969-1]
PIRiT02747.
RefSeqiNP_001034936.1. NM_001039847.2.
NP_002076.2. NM_002085.4. [P36969-1]
UniGeneiHs.433951.

Genome annotation databases

EnsembliENST00000354171; ENSP00000346103; ENSG00000167468. [P36969-1]
ENST00000611653; ENSP00000483655; ENSG00000167468. [P36969-2]
GeneIDi2879.
KEGGihsa:2879.
UCSCiuc021umg.3. human. [P36969-1]

Keywords - Coding sequence diversityi

Alternative initiation, Polymorphism, Selenocysteine

Cross-referencesi

Web resourcesi

NIEHS-SNPs

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X71973 mRNA. Translation: CAA50793.1.
AF060972 Genomic DNA. Translation: AAC32261.1.
AY324108 Genomic DNA. Translation: AAP72965.1.
AC004151 Genomic DNA. Translation: AAC03239.1.
AC005390 Genomic DNA. Translation: AAC28920.1.
BC011836 mRNA. Translation: AAH11836.1.
BC021567 mRNA. Translation: AAH21567.1.
BC022071 mRNA. Translation: AAH22071.1.
BC032695 mRNA. Translation: AAH32695.3.
BC039849 mRNA. Translation: AAH39849.1.
CCDSiCCDS42457.1. [P36969-1]
PIRiT02747.
RefSeqiNP_001034936.1. NM_001039847.2.
NP_002076.2. NM_002085.4. [P36969-1]
UniGeneiHs.433951.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2GS3X-ray1.90A36-197[»]
2OBIX-ray1.55A29-197[»]
ProteinModelPortaliP36969.
SMRiP36969.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109137. 39 interactors.
IntActiP36969. 6 interactors.
STRINGi9606.ENSP00000346103.

Chemistry databases

DrugBankiDB00143. Glutathione.
SwissLipidsiSLP:000001633.

Protein family/group databases

MoonProtiP36969.
PeroxiBasei3603. HsGPx04-A.
3632. HsGPx04-B.
3633. HsGPx04-C.

PTM databases

iPTMnetiP36969.
PhosphoSitePlusiP36969.
SwissPalmiP36969.

Polymorphism and mutation databases

BioMutaiGPX4.
DMDMi172045844.

2D gel databases

REPRODUCTION-2DPAGEIPI00304814.
UCD-2DPAGEP36969.

Proteomic databases

EPDiP36969.
MaxQBiP36969.
PaxDbiP36969.
PeptideAtlasiP36969.
PRIDEiP36969.

Protocols and materials databases

DNASUi2879.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000354171; ENSP00000346103; ENSG00000167468. [P36969-1]
ENST00000611653; ENSP00000483655; ENSG00000167468. [P36969-2]
GeneIDi2879.
KEGGihsa:2879.
UCSCiuc021umg.3. human. [P36969-1]

Organism-specific databases

CTDi2879.
DisGeNETi2879.
GeneCardsiGPX4.
HGNCiHGNC:4556. GPX4.
HPAiCAB008630.
HPA058546.
MalaCardsiGPX4.
MIMi138322. gene.
250220. phenotype.
neXtProtiNX_P36969.
OpenTargetsiENSG00000167468.
Orphaneti93317. Spondylometaphyseal dysplasia, Sedaghatian type.
PharmGKBiPA28952.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1651. Eukaryota.
COG0386. LUCA.
GeneTreeiENSGT00760000119230.
HOGENOMiHOG000277054.
HOVERGENiHBG004333.
InParanoidiP36969.
KOiK05361.
OMAiMSLGRLC.
PhylomeDBiP36969.
TreeFamiTF338735.

Enzyme and pathway databases

BioCyciMetaCyc:HS09562-MONOMER.
ZFISH:HS09562-MONOMER.
BRENDAi1.11.1.12. 2681.
ReactomeiR-HSA-2142688. Synthesis of 5-eicosatetraenoic acids.
R-HSA-2142712. Synthesis of 12-eicosatetraenoic acid derivatives.
R-HSA-2142770. Synthesis of 15-eicosatetraenoic acid derivatives.
SABIO-RKP36969.

Miscellaneous databases

ChiTaRSiGPX4. human.
EvolutionaryTraceiP36969.
GeneWikiiGPX4.
GenomeRNAii2879.
PROiP36969.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000167468.
CleanExiHS_GPX4.
ExpressionAtlasiP36969. baseline and differential.
GenevisibleiP36969. HS.

Family and domain databases

CDDicd00340. GSH_Peroxidase. 1 hit.
Gene3Di3.40.30.10. 1 hit.
InterProiIPR000889. Glutathione_peroxidase.
IPR029759. GPX_AS.
IPR029760. GPX_CS.
IPR012336. Thioredoxin-like_fold.
[Graphical view]
PANTHERiPTHR11592. PTHR11592. 1 hit.
PfamiPF00255. GSHPx. 1 hit.
[Graphical view]
PIRSFiPIRSF000303. Glutathion_perox. 1 hit.
SUPFAMiSSF52833. SSF52833. 1 hit.
PROSITEiPS00460. GLUTATHIONE_PEROXID_1. 1 hit.
PS00763. GLUTATHIONE_PEROXID_2. 1 hit.
PS51355. GLUTATHIONE_PEROXID_3. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiGPX4_HUMAN
AccessioniPrimary (citable) accession number: P36969
Secondary accession number(s): O43381, Q6PJ59, Q9UPK2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: February 26, 2008
Last modified: November 30, 2016
This is version 178 of the entry and version 3 of the sequence. [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, Reference proteome

Documents

  1. Human chromosome 19
    Human chromosome 19: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.