Q9GZT9 Q8N3M8 Q9BZS8 Q9BZT0 EGLN1_HUMAN Egl nine homolog 1 1.14.11.29 Hypoxia-inducible factor prolyl hydroxylase 2 HIF-PH2 HIF-prolyl hydroxylase 2 HPH-2 Prolyl hydroxylase domain-containing protein 2 PHD2 SM-20 EGLN1 C1orf12 PNAS-118 PNAS-137 Homo sapiens Human Eukaryota Metazoa Chordata Craniata Vertebrata Euteleostomi Mammalia Eutheria Euarchontoglires Primates Haplorrhini Catarrhini Hominidae Homo Mapping, characterization, and expression analysis of the SM-20 human homologue, C1orf12, and identification of a novel related gene, SCAND2. NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1) TISSUE SPECIFICITY Characterization and comparative analysis of the EGLN gene family. NUCLEOTIDE SEQUENCE (ISOFORM 1) Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3) TISSUE SPECIFICITY SUBSTRATE SPECIFICITY Aorta Colon Lung The full-ORF clone resource of the German cDNA consortium. NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 160-426 (ISOFORM 1) Amygdala The DNA sequence and biological annotation of human chromosome 1. NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA] Human acute promyelocytic leukemia cell line NB4's apoptosis related genes. NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 136-426 (ISOFORM 2) Promyelocytic leukemia HIF-1, O(2), and the 3 PHDs: how animal cells signal hypoxia to the nucleus. REVIEW C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. FUNCTION Sequence determinants in hypoxia-inducible factor-1alpha for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. FUNCTION SUBSTRATE RECOGNITION MOTIF Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. FUNCTION Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia-inducible transcription factors. TISSUE SPECIFICITY Differential regulation of HIF-1alpha prolyl-4-hydroxylase genes by hypoxia in human cardiovascular cells. TISSUE SPECIFICITY ACTIVITY REGULATION Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. SUBCELLULAR LOCATION INDUCTION Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. INDUCTION SUBSTRATE SPECIFICITY The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). INTERACTION WITH ING4 FUNCTION Kinetic rationale for selectivity toward N- and C-terminal oxygen-dependent degradation domain substrates mediated by a loop region of hypoxia-inducible factor prolyl hydroxylases. SUBSTRATE SPECIFICITY IDENTIFICATION BY MASS SPECTROMETRY MUTAGENESIS OF 237-ASP--ILE-251 DOMAIN Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2 CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS] IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS] Cellular oxygen sensing: Importins and exportins are mediators of intracellular localisation of prolyl-4-hydroxylases PHD1 and PHD2. SUBCELLULAR LOCATION Role of the intracellular localization of HIF-prolyl hydroxylases. SUBCELLULAR LOCATION FUNCTION Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline. INTERACTION WITH EPAS1 Evidence for the slow reaction of hypoxia-inducible factor prolyl hydroxylase 2 with oxygen. ACTIVITY REGULATION Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. POLYMORPHISM Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-125 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS] Cervix carcinoma Genetic evidence for high-altitude adaptation in Tibet. POLYMORPHISM Initial characterization of the human central proteome. IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS] Prolyl hydroxylase-2 (PHD2) exerts tumor-suppressive activity in pancreatic cancer. FUNCTION INDUCTION The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. INTERACTION WITH LIMD1 IDENTIFICATION IN A COMPLEX WITH LIMD1; VHL; ELOB AND CUL2 N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB. ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2 CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS] IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS] A mechanism for induction of a hypoxic response by vaccinia virus. FUNCTION INTERACTION WITH VACCINIA VIRUS PROTEIN C16 (MICROBIAL INFECTION) Toward a comprehensive characterization of a human cancer cell phosphoproteome. PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-12 AND SER-125 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS] Cervix carcinoma Erythroleukemia SIRT2 regulates tumour hypoxia response by promoting HIF-1alpha hydroxylation. INTERACTION WITH HIF1A Myeloid translocation gene-16 co-repressor promotes degradation of hypoxia-inducible factor 1. INTERACTION WITH CBFA2T3 AND HIF1A Cellular oxygen sensing: crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2). X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 181-417 IN COMPLEXES WITH IRON AND COMPETITIVE INHIBITOR METAL-BINDING SITES MUTAGENESIS OF TYR-303 AND ARG-383 SUBUNIT COFACTOR Structural basis for binding of hypoxia-inducible factor to the oxygen-sensing prolyl hydroxylases. X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 181-426 OF WILD TYPE AND MUTANTS ALA-252; ALA-254; LYS-254 AND ALA-398 IN COMPLEX WITH HIF1A IRON N-OXALYGLYCINE AND MANGANESE METAL-BINDING SITES COFACTOR Studies on the reaction of nitric oxide with the hypoxia-inducible factor prolyl hydroxylase domain 2 (EGLN1). X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 181-426 IN COMPLEX WITH NITRIC OXIDE OR A NITRIC OXIDE TRANSFER REAGENT IDENTIFICATION BY MASS SPECTROMETRY S-NITROSYLATION AT CYS-201; CYS-208; CYS-302; CYS-323 AND CYS-326 MUTAGENESIS OF CYS-201; CYS-208; CYS-266; CYS-283; CYS-302; CYS-323 AND CYS-326 1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction. X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 181-416 IN COMPLEX WITH INHIBITOR AND IRON COFACTOR A family with erythrocytosis establishes a role for prolyl hydroxylase domain protein 2 in oxygen homeostasis. VARIANT ECYT3 ARG-317 CHARACTERIZATION OF VARIANT ECYT3 ARG-317 A novel erythrocytosis-associated PHD2 mutation suggests the location of a HIF binding groove. VARIANT ECYT3 HIS-371 CHARACTERIZATION OF VARIANT EXCYT3 HIS-371 Defective Tibetan PHD2 binding to p23 links high altitude adaption to altered oxygen sensing. VARIANTS GLU-4 AND SER-127 POLYMORPHISM INTERACTION WITH PTGES3 CHARACTERIZATION OF VARIANTS GLU-4 AND SER-127 A genetic mechanism for Tibetan high-altitude adaptation. VARIANTS GLU-4 AND SER-127 FUNCTION CATALYTIC ACTIVITY BIOPHYSICOCHEMICAL PROPERTIES POLYMORPHISM CHARACTERIZATION OF VARIANTS GLU-4 AND SER-127 Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. 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. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferentially recognized via a LXXLAP motif. L-prolyl-[hypoxia-inducible factor alpha subunit] + 2-oxoglutarate + O2 = trans-4-hydroxy-L-prolyl-[hypoxia-inducible factor alpha subunit] + succinate + CO2 Fe(2+) Binds 1 Fe(2+) ion per subunit. L-ascorbate Following exposure to hypoxia, activated in HeLa cells but not in cardiovascular cells. 70 nM for HIF2A 150 uM for O(2) 1.3 uM for 2-oxoglutarate Monomer. Interacts with ING4; the interaction inhibits the hydroxylation of HIF alpha proteins. Interacts with PTGES3 (via PXLE motif); thereby recruiting EGLN1 to the HSP90 pathway to facilitate HIF alpha proteins hydroxylation. Interacts with LIMD1. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with EPAS1. Interacts with CBFA2T3 (PubMed:25974097). Interacts with HIF1A (PubMed:25974097). (Microbial infection) Interacts with vaccinia virus protein C16; this interaction inhibits PHD2-dependent hydroxylation of HIF-1alpha. Q9GZT9 Q02410 false 2 Q9GZT9 Q99767 false 2 Q9GZT9 Q12959 false 3 Q9GZT9 Q92796 false 3 Q9GZT9 P78352 false 3 Q9GZT9 Q99814 false 3 Q9GZT9 Q14318 false 6 Q9GZT9 Q68DX3 false 3 Q9GZT9 A4D2P6 false 2 Q9GZT9 Q9Y3R0 false 5 Q9GZT9 Q9C0E4 false 5 Q9GZT9 Q16665 false 6 Q9GZT9 Q14005 false 2 Q9GZT9 Q8TBB1 false 3 Q9GZT9 Q8N448 false 2 Q9GZT9 Q96QZ7 false 2 Q9GZT9 Q86UL8 false 5 Q9GZT9 O75970 false 3 Q9GZT9 Q86UT5 false 2 Q9GZT9 Q13438 false 4 Q9GZT9 Q8NI35 false 9 Q9GZT9 Q5T2W1 false 3 Q9GZT9 Q14160 false 3 Q9GZT9 Q07157 false 2 Q9GZT9 Q9P202 false 2 Q9GZT9 PRO_0000037551 true 3 Cytoplasm Nucleus Mainly cytoplasmic. Shuttles between the nucleus and cytoplasm (PubMed:19631610). Nuclear export requires functional XPO1. Q9GZT9-1 1 Q9GZT9-2 2 Q9GZT9-3 3 According to PubMed:11056053, widely expressed with highest levels in skeletal muscle and heart, moderate levels in pancreas, brain (dopaminergic neurons of adult and fetal substantia nigra) and kidney, and lower levels in lung and liver. According to PubMed:12351678 widely expressed with highest levels in brain, kidney and adrenal gland. Expressed in cardiac myocytes, aortic endothelial cells and coronary artery smooth muscle. According to PubMed:12788921; expressed in adult and fetal heart, brain, liver, lung, skeletal muscle and kidney. Also expressed in placenta. Highest levels in adult heart, brain, lung and liver and fetal brain, heart spleen and skeletal muscle. The beta(2)beta(3) 'finger-like' loop domain is important for substrate (HIFs' CODD/NODD) selectivity. S-nitrosylation inhibits the enzyme activity up to 60% under aerobic conditions. Chelation of Fe(2+) has no effect on the S-nitrosylation. It is uncertain whether nitrosylation occurs on Cys-323 or Cys-326. Variations in EGLN1 are associated with adaptation to high altitude (PubMed:20466884, PubMed:20838600, PubMed:24711448, PubMed:25129147). High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body and leads to an elevation of hematocrit levels and an increased number of erythrocytes (polycythemia) in non-adapted individuals. Genetic variations in EGLN1 contribute to adaptation to high altitute by maintaining hematocrit levels comparable to those for populations living at sea level and are present in two high-altitude regions where humans have lived for millennia, the Andean Altiplano and the Tibetan Plateau (PubMed:20466884, PubMed:20838600). Variants Glu-4 and Ser-127, which are frequently associated together and are present in the majority of Tibetan populations, participate in adaptation to high altitude (PubMed:24711448, PubMed:25129147). Molecular mechanisms explaining this adaptation are however unclear. According to a report, variants Glu-4 and Ser-127 lead to decreased interaction with PTGES3 and subsequent decrease of HIF alpha proteins degradation (PubMed:24711448). According to a second report, Glu-4 and Ser-127 haplotype enhances the catalytic activity under hypoxic conditions, promoting increased HIF alpha proteins degradation, thereby abrogating hypoxia-induced and HIF alpha-mediated augmentation of erythropoiesis and protecting Tibetans from polycythemia at high altitude (PubMed:25129147). Erythrocytosis, familial, 3 ECYT3 An autosomal dominant disorder characterized by elevated serum hemoglobin and hematocrit, and normal serum erythropoietin levels. The disease is caused by variants affecting the gene represented in this entry. Isoform 2 Inactive isoform. It was previously reported that this protein was the ortholog of rat SM-20. However, EGLN3 is now considered the true ortholog of rat SM-20 since it shows substantially greater similarity. Truncated N-terminus. 3D-structure Acetylation Alternative splicing Congenital erythrocytosis Cytoplasm Dioxygenase Disease variant Iron Metal-binding Nucleus Oxidoreductase Phosphoprotein Proteomics identification Reference proteome S-nitrosylation Vitamin C Zinc Zinc-finger Zn(2+) Zn(2+) Zn(2+) Zn(2+) Zn(2+) Zn(2+) Zn(2+) Zn(2+) Fe cation Fe cation Fe cation 2-oxoglutarate CQGSEGALGHGVGPHQHSGPAPPAAVPPPRAGAREPRKAAARRDNASGDAAKGKVKAKPPADPAAAASPCRAAAGGQGSAVAAEAEPGKEEPPARSSLFQEKANLYPPSNTPGDALSP LLGGYRFAFSWNSDERA D E C S P R R H C A C A R A D A K C A C A C A Y F C A C A R A MANDSGGPGGPSPSERDRQYCELCGKMENLLRCSRCRSSFYCCKEHQRQDWKKHKLVCQGSEGALGHGVGPHQHSGPAPPAAVPPPRAGAREPRKAAARRDNASGDAAKGKVKAKPPADPAAAASPCRAAAGGQGSAVAAEAEPGKEEPPARSSLFQEKANLYPPSNTPGDALSPGGGLRPNGQTKPLPALKLALEYIVPCMNKHGICVVDDFLGKETGQQIGDEVRALHDTGKFTDGQLVSQKSDSSKDIRGDKITWIEGKEPGCETIGLLMSSMDDLIRHCNGKLGSYKINGRTKAMVACYPGNGTGYVRHVDNPNGDGRCVTCIYYLNKDWDAKVSGGILRIFPEGKAQFADIEPKFDRLLFFWSDRRNPHEVQPAYATRYAITVWYFDADERARAKVKYLTGEKGVRVELNKPSDSVGKDVF Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms Distributed under the Creative Commons Attribution (CC BY 4.0) License