Prolyl hydroxylase EGLN2 (EGLN2)
The protein contains 407 amino acids for an estimated molecular weight of 43650 Da.
Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as ATF4, IKBKB, CEP192 and HIF1A (PubMed:11595184, PubMed:12039559, PubMed:15925519, PubMed:16509823, PubMed:17114296, PubMed:23932902). Target proteins are preferentially recognized via a LXXLAP motif (PubMed:11595184, PubMed:12039559, PubMed:15925519). Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins (PubMed:11595184, PubMed:12039559, PubMed:12181324, PubMed:15925519, PubMed:19339211). Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A (PubMed:11595184, PubMed:12039559, PubMed:12181324, PubMed:15925519). Also hydroxylates HIF2A (PubMed:11595184, PubMed:12039559, PubMed:15925519). Has a preference for the CODD site for both HIF1A and HIF2A (PubMed:11595184, PubMed:12039559, PubMed:15925519). Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex (PubMed:11595184, PubMed:12039559, PubMed:15925519). Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes (PubMed:11595184, PubMed:12039559, PubMed:15925519). EGLN2 is involved in regulating hypoxi (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.
- 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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Biological Process
Cell redox homeostasis
Cellular response to hypoxia
Intracellular estrogen receptor signaling pathway
Peptidyl-proline hydroxylation to 4-hydroxy-L-proline
Positive regulation of protein catabolic process
Regulation of cell growth
Regulation of neuron apoptotic process
Regulation of transcription from RNA polymerase II promoter in response to hypoxia
Response to hypoxia
The reference OMIM entry for this protein is 606424
Egl9, c. elegans, homolog of, 2; egln2
Prolyl hydroxylase domain-containing protein 1; phd1
Hypoxia-inducible factor prolyl 4-hydroxylase 1; hifph1; hifp4h1
Hif prolyl 4-hydroxylase 1
CLONING
HIF is a transcriptional complex that plays a central role in mammalian oxygen homeostasis. Posttranslational modification by prolyl hydroxylation is a key regulatory event that targets HIF-alpha (HIF1; 603348) subunits for proteasomal destruction via the von Hippel-Lindau (VHL; 608537) ubiquitylation complex. Epstein et al. (2001) defined a conserved HIF-VHL-prolyl hydroxylase pathway in C. elegans and identified Egl9 as a dioxygenase that regulates HIF by prolyl hydroxylation. In mammalian cells, they showed that the HIF-prolyl hydroxylases are represented by 3 proteins with a conserved 2-histidine-1-carboxylate iron coordination motif at the catalytic site. The genes encoding these proteins were cloned and termed PHD1, PHD2 (606425), and PHD3 (606426) by the authors. Direct modulation of recombinant enzyme activity by graded hypoxia, iron chelation, and cobaltous ions mirrored the characteristics of HIF induction in vivo, fulfilling requirements for these enzymes being oxygen sensors that regulate HIF. Bruick and McKnight (2001) independently identified the conserved family of HIF prolyl hydroxylase enzymes, which they called HPH1, 2, and 3, respectively, that appear to be responsible for the posttranslational modification of HIF that targets it for ubiquitination. By quantitative RT-PCR, Oehme et al. (2002) found highest EGLN2 expression in testis, with much lower expression in the 16 other human tissues examined. Independently, Hirsila et al. (2003) cloned HIFP4H1, HIFP4H2, and HIFP4HD3 by PCR of human colon, aorta, and lung cDNA. The deduced 407-amino acid HIFP4H1 protein contains a C-terminal catalytic domain with motifs for binding iron and the C5 carboxyl group of 2-oxoglutarate. PCR analysis of adult and fetal samples revealed HIFP4H1 expression in all tissues examined, with highest expression in adult brain, placenta, lung, and kidney.GENE FUNCTION
In cultured mammalian cells, Bruick and McKnight (2001) found that the inappropriate accumulation of HIF caused by forced expression of the HIF1-alpha subunit under normoxic conditions was attenuated by coexpression of HPH. Suppression of HPH in cultured Drosophila melanogaster cells by RNA interference resulted in elevated expression of the hypoxia-inducible gene LDH (see 150000) under normoxic conditions. Bruick and McKnight (2001) concluded that HPH is an essential component of the pathway through which cells sense oxygen. Using recombinant proteins expressed in insect cells, Hirsila et al. (2003) found that HIFP4H1, HIFP4H2, and HIFP4H3 showed in vitro 2-oxoglutarate-dependent hydroxylation of a 19-residue peptide corresponding to the C-terminal prolyl hydroxylation site of HIF1-alpha. All 3 enzymes showed lower or no activity against a peptide corresponding to a more N-terminal putative prolyl hydroxylation site in HIF1-alpha. All 3 enzymes hydroxylated peptides designed from putative prolyl hydroxylation sites of human HIF2-alpha (EPAS1; 603349), HIF3-alpha (HIF3A; 609976), and C. elegans HIF-alpha. Nakayama et al. (2004) demonstrated that PHD1 and PHD3 abundance is regulated via their targeting for proteasome-dependent degradation by the E3 ubiquitin ligases SIAH1 (602212) and SIAH2 (602213) under hypoxia conditions. Siah2-null mouse fibroblasts exhibited prolonged Phd3 half-life, resulting in lower levels of Hif1a expression during hypoxia. Hypoxia-induced Hif1a expression was completely inhibited in Siah1a/Siah2-null cells, yet could be rescu ... More on the omim web site
June 29, 2020: 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 25, 2017: Additional information
No protein expression data in P. Mayeux work for EGLN2
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 606424 was added.
Feb. 24, 2016: Protein entry updated
Automatic update: model status changed