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Protein

Phospholipid hydroperoxide glutathione peroxidase

Gene

Gpx4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins (PubMed:29290465). Can also reduce fatty acid hydroperoxide, cholesterol hydroperoxide and thymine hydroperoxide (By similarity). Plays a key role in protecting cells from oxidative damage by preventing membrane lipid peroxidation (PubMed:12566075). Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron-dependent accumulation of lipid reactive oxygen species (PubMed:12566075, PubMed:24439385, PubMed:25402683, PubMed:25922076, PubMed:29290465). The presence of selenocysteine (Sec) versus Cys at the active site is essential for life: it provides resistance to overoxidation and prevents cells against ferroptosis (PubMed:29290465). The presence of Sec at the active site is also essential for the survival of a specific type of parvalbumin-positive interneurons, thereby preventing against fatal epileptic seizures (PubMed:29290465). May be required to protect cells from the toxicity of ingested lipid hydroperoxides (PubMed:12566075). Required for normal sperm development and male fertility (PubMed:19783653, PubMed:25922076). Essential for maturation and survival of photoreceptor cells (PubMed:22207760). Plays a role in a primary T-cell response to viral and parasitic infection by protecting T-cells from ferroptosis and by supporting T-cell expansion (PubMed:25824823).By similarity9 Publications
Isoform Cytoplasmic: Specifically able to suppress the production of leukotriene and prostaglandin in response to several stimuli by reducing fatty acid hydroperoxide.By similarity
Isoform Mitochondrial: Specifically required to prevent mitochondrial cell death by mediating reduction of cardiolipin hydroperoxide (By similarity). Also required for normal sperm development and male fertility (PubMed:19417079).By similarity1 Publication
Isoform Nuclear: Required for male fertility by stabilizing the condensed chromatin in sperm nuclei (PubMed:12566075).1 Publication

Miscellaneous

The presence of selenolate in the active site is essential for resistance to overoxidation: in the absence of reducing equivalents, the enzyme can form a selenylamide intermediate during its catalytic cycle, thereby preventing its irreversible overoxidation.1 Publication

Catalytic activityi

2 glutathione + a hydroperoxy-fatty-acyl-[lipid] = glutathione disulfide + a hydroxy-fatty-acyl-[lipid] + H2O.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei731 Publication1

GO - Molecular functioni

  • glutathione peroxidase activity Source: MGI
  • identical protein binding Source: MGI
  • phospholipid-hydroperoxide glutathione peroxidase activity Source: UniProtKB

GO - Biological processi

  • chromatin organization Source: MGI
  • multicellular organism development Source: UniProtKB-KW
  • negative regulation of ferroptosis Source: UniProtKB
  • protein polymerization Source: MGI
  • response to oxidative stress Source: UniProtKB
  • spermatogenesis Source: MGI

Keywordsi

Molecular functionDevelopmental protein, Oxidoreductase, Peroxidase

Enzyme and pathway databases

BRENDAi1.11.1.12 3474
ReactomeiR-MMU-2142712 Synthesis of 12-eicosatetraenoic acid derivatives
R-MMU-2142770 Synthesis of 15-eicosatetraenoic acid derivatives

Protein family/group databases

PeroxiBasei3714 MmGPx04-A
3865 MmGPx04-B
3867 MmGPx04-C

Names & Taxonomyi

Protein namesi
Recommended name:
Phospholipid hydroperoxide glutathione peroxidase2 Publications (EC:1.11.1.121 Publication)
Short name:
PHGPx2 Publications
Alternative name(s):
Glutathione peroxidase 41 Publication
Short name:
GPx-41 Publication
Short name:
GSHPx-41 Publication
Gene namesi
Name:Gpx41 PublicationImported
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:104767 Gpx4

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, Nucleus

Pathology & Biotechi

Disruption phenotypei

Embryonic lethality in utero at midgestation, caused by inability to initiate gastrulation and the absence of embryonic cavities (PubMed:12745070). Isoform mitochondrial: Selective disruption of isoform mitochondrial causes sperm abnormalities and male infertility (PubMed:19417079). Conditional knockout mice lacking Gpx4 in spermatocytes causes sperm abnormalities and male infertility (PubMed:19783653). Conditional knockout mice lacking Gpx4 in photoreceptor cells causes retinal degeneration, decreased mitochondrial biomass and decreased number of connecting cilia in these cells (PubMed:22207760). Mice display neurodegeneration (PubMed:18762024). Conditional knockout mice lacking Gpx4 in neurons show reduced parvalbumin-positive interneurons and develop phenotypes, such as cerebellar hypoplasia and seizures (PubMed:19890015, PubMed:24599700). Induced disruption of Gpx4 in mice causes acute renal failure and early death due to ferroptosis (PubMed:25402683).8 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi73U → C: Mice develop normally and were born at the expected Mendelian ratio. Homozygous mice however lose body weight by P14-P16 and are susceptible to fatal epileptic seizures. Cells are extremely sensitive to peroxide-induced cell death because the enzyme is inactivated: The enzyme undergoes overoxidation and irreversible inactivation in the presence of exceeding concentrations of its substrates. Unlike the wild-type enzyme, which can form a selenylamide in the absence of reducing equivalents, thereby preventing its irreversible overoxidation, the mutant fails to form such an intermediate during its catalytic cycle. 1 Publication1
Mutagenesisi73U → S: Early embryonic lethality in homozygous mice. Male subfertility in heterozygous mice due to impaired spermatogenesis. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_0000013069? – 197Phospholipid hydroperoxide glutathione peroxidase
Transit peptidei1 – ?MitochondrionSequence analysis

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei40PhosphoserineBy similarity1

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiQ91XR9
PeptideAtlasiO70325
PRIDEiO70325

PTM databases

iPTMnetiO70325
PhosphoSitePlusiQ91XR9
SwissPalmiO70325

Expressioni

Tissue specificityi

Widely expressed with the highest levels in testis, heart, cerebrum, ileum, stomach, liver, jejunum and epididymis (PubMed:17503194). Expressed primarily in testis and sperm midpiece (at protein level) (PubMed:19417079, PubMed:12566075). Expressed in brain (at protein level) (PubMed:22207760, PubMed:12566075). Expressed in heart, liver and kidney (at protein level) (PubMed:12566075). Expressed in retina, especially in inner segments of photoreceptor cells (at protein level) (PubMed:22207760). Isoform Mitochondrial and isoform Cytoplasmic: Highly expressed during embryogenesis, while isoform Nuclear is weakly expressed (PubMed:1668477). Isoform Mitochondrial and isoform Nuclear are down-regulated between E14.5 and E17.5, while isoform Cytoplasmic remains constant (PubMed:1668477). Isoform Nuclear: Mainly expressed in sperm (PubMed:11344099).6 Publications

Gene expression databases

BgeeiENSMUSG00000075706
CleanExiMM_GPX4
ExpressionAtlasiO70325 baseline and differential
GenevisibleiO70325 MM

Interactioni

Subunit structurei

Monomer. Has a tendency to form higher mass oligomers.By similarity

GO - Molecular functioni

Protein-protein interaction databases

BioGridi551619, 2 interactors
IntActiO70325, 1 interactor

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
Turni91 – 94Combined sources4
Beta strandi95 – 101Combined sources7
Turni104 – 107Combined sources4
Helixi113 – 122Combined sources10
Beta strandi127 – 130Combined sources4
Helixi142 – 148Combined sources7
Helixi151 – 153Combined sources3
Beta strandi156 – 160Combined sources5
Beta strandi167 – 170Combined sources4
Beta strandi176 – 180Combined sources5
Helixi187 – 190Combined sources4
Helixi191 – 195Combined sources5

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5L71X-ray1.80A29-197[»]
ProteinModelPortaliO70325
SMRiO70325
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the glutathione peroxidase family.Curated

Keywords - Domaini

Transit peptide

Phylogenomic databases

eggNOGiKOG1651 Eukaryota
COG0386 LUCA
GeneTreeiENSGT00760000119230
HOGENOMiHOG000277054
HOVERGENiHBG004333
InParanoidiQ91XR9
KOiK05361
OMAiYVNYGVT

Family and domain databases

CDDicd00340 GSH_Peroxidase, 1 hit
InterProiView protein in InterPro
IPR000889 Glutathione_peroxidase
IPR029759 GPX_AS
IPR029760 GPX_CS
IPR036249 Thioredoxin-like_sf
PANTHERiPTHR11592 PTHR11592, 1 hit
PfamiView protein in Pfam
PF00255 GSHPx, 1 hit
PIRSFiPIRSF000303 Glutathion_perox, 1 hit
PRINTSiPR01011 GLUTPROXDASE
SUPFAMiSSF52833 SSF52833, 1 hit
PROSITEiView protein in PROSITE
PS00460 GLUTATHIONE_PEROXID_1, 1 hit
PS00763 GLUTATHIONE_PEROXID_2, 1 hit
PS51355 GLUTATHIONE_PEROXID_3, 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 and alternative initiation. AlignAdd to basket

Isoform Mitochondrial (identifier: O70325-1) [UniParc]FASTAAdd to basket
Also known as: mGPx41 Publication

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
MSWGRLSRLL KPALLCGALA APGLAGTMCA SRDDWRCARS MHEFSAKDID
60 70 80 90 100
GHMVCLDKYR GFVCIVTNVA SQUGKTDVNY TQLVDLHARY AECGLRILAF
110 120 130 140 150
PCNQFGRQEP GSNQEIKEFA AGYNVKFDMY SKICVNGDDA HPLWKWMKVQ
160 170 180 190
PKGRGMLGNA IKWNFTKFLI DKNGCVVKRY GPMEEPQVIE KDLPCYL
Length:197
Mass (Da):22,229
Last modified:February 26, 2008 - v4
Checksum:i5CED4991A484F31C
GO
Isoform Cytoplasmic (identifier: O70325-2) [UniParc]FASTAAdd to basket
Also known as: cGPx41 Publication

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

Note: Produced by alternative initiation at Met-28 of isoform Mitochondrial.
Show »
Length:170
Mass (Da):19,522
Checksum:i89AD1F6B28946C95
GO
Isoform Nuclear (identifier: O70325-3) [UniParc]FASTAAdd to basket
Also known as: nGPx41 Publication

The sequence of this isoform differs from the canonical sequence as follows:
     1-28: MSWGRLSRLLKPALLCGALAAPGLAGTM → MGRAAARKRG...YCNSSEFLGL

Show »
Length:253
Mass (Da):29,194
Checksum:iC55E2827533CDBF3
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti39R → A in BAA22780 (PubMed:9370288).Curated1
Sequence conflicti176V → E in AAK74112 (PubMed:11344099).Curated1
Sequence conflicti191K → R in AAK74112 (PubMed:11344099).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0593491 – 28MSWGR…LAGTM → MGRAAARKRGRCRQRGGSPR GRRRRGPGRQSPRKRPGPRR RKARARRRRRARPRRMEPIP EPFNPGPLLQEPPQYCNSSE FLGL in isoform Nuclear. Add BLAST28
Alternative sequenceiVSP_0187431 – 27Missing in isoform Cytoplasmic. CuratedAdd BLAST27

Non-standard residue

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Non-standard residuei73Selenocysteine1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
D87896 mRNA Translation: BAA22780.1
AJ012104 Genomic DNA Translation: CAB42657.2
AF045768 mRNA Translation: AAC15832.1
AF045769 mRNA Translation: AAC15833.1
AF274027 mRNA Translation: AAK74112.1
AF044056 Genomic DNA Translation: AAC14560.1
AB030643 Genomic DNA Translation: BAC06507.1
AB030643 Genomic DNA Translation: BAC06508.1
AB030643 Genomic DNA Translation: BAC06509.1
AB030728 Genomic DNA Translation: BAC06511.1
AK006441 mRNA Translation: BAC55251.1
CCDSiCCDS24007.1 [O70325-3]
CCDS35973.1 [O70325-1]
RefSeqiNP_001032830.2, NM_001037741.3 [O70325-3]
NP_032188.3, NM_008162.3 [O70325-1]
UniGeneiMm.332810
Mm.359573

Genome annotation databases

EnsembliENSMUST00000097227; ENSMUSP00000094863; ENSMUSG00000075706 [O70325-3]
ENSMUST00000105372; ENSMUSP00000101011; ENSMUSG00000075706 [O70325-1]
GeneIDi625249
KEGGimmu:625249
UCSCiuc007gbk.2 mouse [O70325-1]

Keywords - Coding sequence diversityi

Alternative initiation, Alternative splicing, Selenocysteine

Similar proteinsi

Entry informationi

Entry nameiGPX4_MOUSE
AccessioniPrimary (citable) accession number: O70325
Secondary accession number(s): O35560
, Q8K4U8, Q91XR9, Q9JK35
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 11, 2001
Last sequence update: February 26, 2008
Last modified: April 25, 2018
This is version 169 of the entry and version 4 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
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Main funding by: National Institutes of Health