Phospholipid hydroperoxide glutathione peroxidase (GPX4)
The protein contains 197 amino acids for an estimated molecular weight of 22175 Da.
Essential antioxidant peroxidase that directly reduces phospholipid hydroperoxide even if they are incorporated in membranes and lipoproteins (By similarity). 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 (By similarity). Required to prevent cells from ferroptosis, a non-apoptotic cell death resulting from an iron-dependent accumulation of lipid reactive oxygen species (PubMed:24439385). 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 (By similarity). 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 (By similarity). May be required to protect cells from the toxicity of ingested lipid hydroperoxides (By similarity). Required for normal sperm development and male fertility (By similarity). Essential for maturation and survival of photoreceptor cells (By similarity). 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 (By similarity). Plays a role of glutathione peroxidase in platelets in the arachidonic acid metabolism (PubMed:11115402). Reduces hydroperoxy ester lipid (updated: June 17, 2020)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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| Variant | Description |
|---|---|
| dbSNP:rs8178967 | |
| a patient affected by cryptorchidism |
Biological Process
Aging
Arachidonic acid metabolic process
Chromatin organization
Glutathione metabolic process
Hydrogen peroxide catabolic process
Lipoxygenase pathway
Long-chain fatty acid biosynthetic process
Multicellular organism development
Negative regulation of ferroptosis
Oxidation-reduction process
Phospholipid metabolic process
Protein polymerization
Regulation of inflammatory response
Response to estradiol
Response to oxidative stress
Small molecule metabolic process
Spermatogenesis
The reference OMIM entry for this protein is 138322
Glutathione peroxidase 4; gpx4
Phospholipid hydroperoxide glutathione peroxidase; phgpx
DESCRIPTION
GPX4 reduces phospholipid hydroperoxides within membranes and lipoproteins and acts in conjunction with alpha-tocopherol to inhibit lipid peroxidation. Lipid peroxidation is implicated in a number of pathophysiologic processes, including inflammation and atherogenesis. GPX4 is a selenoprotein whose production and activity are sensitive to selenium (Se), which is incorporated into selenoproteins as selenocysteine (summary by Sneddon et al., 2003).CLONING
Using porcine Phgpx to screen a testis cDNA library, Esworthy et al. (1994) cloned human GPX4, which they called PHGPX. The 3-prime UTR contains a selenocysteine insertion sequence (SECIS) required for insertion of selenocysteine at an opal codon (UGA). The deduced 197-amino acid protein has a calculated molecular mass of 19 kD. It has putative active-site tryptophan and glutamic acid residues that are predicted to interact with selenocysteine, and a tyrosine residue that is phosphorylated in the porcine protein. By fractionation and immunofluorescence microscopy of resting human platelets, Januel et al. (2006) showed that GPX4 associated with membranes, cytoplasm, and mitochondria, and that GPX4 activity showed an identical distribution. Western blot analysis detected GPX4 at an apparent molecular mass of 20 to 21 kD. Roveri et al. (1992) found that rat Gpx4 was present primarily in testis. Januel et al. (2006) stated that rat has mitochondrial and nonmitochondrial forms of Gpx4. Borchert et al. (2003) characterized the expression of 2 major isoforms of Gpx4 in mouse tissues. One isoform, which they designated the phospholipid (phGpx) form, was expressed in many tissues. The other, designated the sperm nucleus (snGpx) isoform, was detected in mouse testis and kidney, as well as in a human embryonic kidney cell line. Subcellular fractionation and immunoelectron microscopy revealed cytosolic localization. Immunohistochemical staining of mouse kidneys showed staining for snGpx in cortical and medullary interstitial cells. Analysis of the 5-prime flanking region common to both isoforms revealed strong promoter activity. The snGpx4 promoter, which contains 334 bp of intronic sequence, suppressed the activity of the common promoter.BIOCHEMICAL FEATURES
To overcome inefficient selenocysteine-incorporating machinery in recombinant systems, Scheerer et al. (2007) expressed recombinant human cytosolic GPX4 containing a sec46-to-cys (U46C) mutation, which retains residual catalytic activity, in E. coli. They solved the crystal structure of this molecule to 1.55-angstrom resolution. X-ray data indicated that the monomeric protein consisted of 4 alpha helices and 7 beta strands. The catalytic triad (cys46, gln81, and trp136) localized at a flat impression on the protein surface extending into a surface-exposed patch of basic amino acids (lys48, lys135, and arg152) that also contained polar thr139. Mutation analysis confirmed the functional importance of the catalytic triad. Like the wildtype enzyme, the U46C mutant exhibited a strong tendency toward polymerization, which was prevented by reductants. Site-directed mutagenesis suggested involvement of the catalytic cys46 and surface-exposed cys10 and cys66 in polymer formation. In GPX4 crystals, these residues contacted adjacent protein monomers.GENE STRUCTURE
Kelner and Montoya (1998) determined that the human GPX4 gene spans 2.8 kb and contains 7 exons. Analysis of the gene sequence identifi ... More on the omim web site
June 29, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
April 12, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 138322 was added.
Jan. 28, 2016: Protein entry updated
Automatic update: model status changed
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed