EGLN2_RAT
ID EGLN2_RAT Reviewed; 415 AA.
AC Q6AYU4;
DT 25-JAN-2012, integrated into UniProtKB/Swiss-Prot.
DT 13-SEP-2004, sequence version 1.
DT 03-AUG-2022, entry version 126.
DE RecName: Full=Prolyl hydroxylase EGLN2 {ECO:0000305};
DE EC=1.14.11.- {ECO:0000269|PubMed:15925519};
DE AltName: Full=Egl nine homolog 2 {ECO:0000305};
DE EC=1.14.11.29 {ECO:0000255|PROSITE-ProRule:PRU00805, ECO:0000269|PubMed:15925519};
DE AltName: Full=HPH-3;
DE AltName: Full=Hypoxia-inducible factor prolyl hydroxylase 1;
DE Short=HIF-PH1;
DE Short=HIF-prolyl hydroxylase 1;
DE Short=HPH-1;
DE AltName: Full=Prolyl hydroxylase domain-containing protein 1;
DE Short=PHD1;
GN Name=Egln2 {ECO:0000312|RGD:631376};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, COFACTOR,
RP BIOPHYSICOCHEMICAL PROPERTIES, AND TISSUE SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=15925519; DOI=10.1016/j.pep.2005.03.036;
RA Cobb R.R., McClary J., Manzana W., Finster S., Larsen B., Blasko E.,
RA Pearson J., Biancalana S., Kauser K., Bringmann P., Light D.R., Schirm S.;
RT "Cloning and characterization of the rat HIF-1 alpha prolyl-4-hydroxylase-1
RT gene.";
RL Protein Expr. Purif. 42:295-304(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND INDUCTION.
RX PubMed=16765982; DOI=10.1016/j.yjmcc.2006.04.009;
RA Willam C., Maxwell P.H., Nichols L., Lygate C., Tian Y.M., Bernhardt W.,
RA Wiesener M., Ratcliffe P.J., Eckardt K.U., Pugh C.W.;
RT "HIF prolyl hydroxylases in the rat; organ distribution and changes in
RT expression following hypoxia and coronary artery ligation.";
RL J. Mol. Cell. Cardiol. 41:68-77(2006).
CC -!- FUNCTION: Prolyl hydroxylase that mediates hydroxylation of proline
CC residues in target proteins, such as ATF4, IKBKB, CEP192 and HIF1A
CC (PubMed:15925519). Target proteins are preferentially recognized via a
CC LXXLAP motif (By similarity). Cellular oxygen sensor that catalyzes,
CC under normoxic conditions, the post-translational formation of 4-
CC hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins
CC (PubMed:15925519). Hydroxylates a specific proline found in each of the
CC oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-
CC terminal, CODD) of HIF1A (By similarity). Also hydroxylates HIF2A (By
CC similarity). Has a preference for the CODD site for both HIF1A and
CC HIF2A (By similarity). Hydroxylated HIFs are then targeted for
CC proteasomal degradation via the von Hippel-Lindau ubiquitination
CC complex (By similarity). Under hypoxic conditions, the hydroxylation
CC reaction is attenuated allowing HIFs to escape degradation resulting in
CC their translocation to the nucleus, heterodimerization with HIF1B, and
CC increased expression of hypoxy-inducible genes (By similarity). EGLN2
CC is involved in regulating hypoxia tolerance and apoptosis in cardiac
CC and skeletal muscle (By similarity). Also regulates susceptibility to
CC normoxic oxidative neuronal death (By similarity). Links oxygen sensing
CC to cell cycle and primary cilia formation by hydroxylating the critical
CC centrosome component CEP192 which promotes its ubiquitination and
CC subsequent proteasomal degradation (By similarity). Hydroxylates IKBKB,
CC mediating NF-kappa-B activation in hypoxic conditions (By similarity).
CC Also mediates hydroxylation of ATF4, leading to decreased protein
CC stability of ATF4 (By similarity). {ECO:0000250|UniProtKB:Q91YE2,
CC ECO:0000250|UniProtKB:Q96KS0, ECO:0000269|PubMed:15925519}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-prolyl-[protein] + O2 = CO2 + succinate +
CC trans-4-hydroxy-L-prolyl-[protein]; Xref=Rhea:RHEA:63484, Rhea:RHEA-
CC COMP:12408, Rhea:RHEA-COMP:16354, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:50342, ChEBI:CHEBI:61965;
CC Evidence={ECO:0000269|PubMed:15925519};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:63485;
CC Evidence={ECO:0000269|PubMed:15925519};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2-oxoglutarate + L-prolyl-[hypoxia-inducible factor alpha
CC subunit] + O2 = CO2 + succinate + trans-4-hydroxy-L-prolyl-[hypoxia-
CC inducible factor alpha subunit]; Xref=Rhea:RHEA:48400, Rhea:RHEA-
CC COMP:12093, Rhea:RHEA-COMP:12094, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:16810, ChEBI:CHEBI:30031,
CC ChEBI:CHEBI:50342, ChEBI:CHEBI:61965; EC=1.14.11.29;
CC Evidence={ECO:0000269|PubMed:15925519};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00805,
CC ECO:0000269|PubMed:15925519};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000255|PROSITE-
CC ProRule:PRU00805, ECO:0000269|PubMed:15925519};
CC -!- COFACTOR:
CC Name=L-ascorbate; Xref=ChEBI:CHEBI:38290;
CC Evidence={ECO:0000269|PubMed:15925519};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=30 uM for HIF1A DLDLEMLAPYIPMDDDFQL peptide (at pH 7.5 and 37
CC degrees Celsius) {ECO:0000269|PubMed:15925519};
CC KM=25 uM for 2-oxoglutarate {ECO:0000269|PubMed:15925519};
CC KM=55 uM for L-ascorbate (at pH 7.5 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:15925519};
CC KM=1.5 uM for Fe(2+) (at pH 7.5 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:15925519};
CC -!- SUBUNIT: Interacts with E3 ligase SIAH2. Interacts with LIMD1, WTIP and
CC AJUBA. {ECO:0000250|UniProtKB:Q96KS0}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16765982}.
CC -!- TISSUE SPECIFICITY: Expressed in heart, kidney, brain, liver, skeletal
CC muscle, lung and spleen. Highest level in testis.
CC {ECO:0000269|PubMed:15925519, ECO:0000269|PubMed:16765982}.
CC -!- DOMAIN: The beta(2)beta(3) 'finger-like' loop domain is important for
CC substrate (HIFs' CODD/NODD) selectivity.
CC {ECO:0000250|UniProtKB:Q9GZT9}.
CC -!- PTM: Ubiquitinated by SIAH1 and/or SIAH2 in response to the unfolded
CC protein response (UPR), leading to its degradation.
CC {ECO:0000250|UniProtKB:Q91YE2}.
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DR EMBL; AY952204; AAX51892.1; -; mRNA.
DR EMBL; CH473979; EDM07971.1; -; Genomic_DNA.
DR EMBL; BC078907; AAH78907.1; -; mRNA.
DR EMBL; BC081858; AAH81858.1; -; mRNA.
DR RefSeq; NP_001004083.1; NM_001004083.1.
DR RefSeq; XP_006228637.1; XM_006228575.3.
DR AlphaFoldDB; Q6AYU4; -.
DR SMR; Q6AYU4; -.
DR STRING; 10116.ENSRNOP00000028434; -.
DR iPTMnet; Q6AYU4; -.
DR PhosphoSitePlus; Q6AYU4; -.
DR PaxDb; Q6AYU4; -.
DR PRIDE; Q6AYU4; -.
DR Ensembl; ENSRNOT00000028434; ENSRNOP00000028434; ENSRNOG00000020947.
DR GeneID; 308457; -.
DR KEGG; rno:308457; -.
DR UCSC; RGD:631376; rat.
DR CTD; 112398; -.
DR RGD; 631376; Egln2.
DR eggNOG; KOG3710; Eukaryota.
DR GeneTree; ENSGT00940000160655; -.
DR HOGENOM; CLU_063064_0_0_1; -.
DR InParanoid; Q6AYU4; -.
DR OMA; WSIGALM; -.
DR OrthoDB; 1604981at2759; -.
DR TreeFam; TF314595; -.
DR Reactome; R-RNO-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR PRO; PR:Q6AYU4; -.
DR Proteomes; UP000002494; Chromosome 1.
DR Proteomes; UP000234681; Chromosome 1.
DR Bgee; ENSRNOG00000020947; Expressed in testis and 19 other tissues.
DR Genevisible; Q6AYU4; RN.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0016706; F:2-oxoglutarate-dependent dioxygenase activity; ISO:RGD.
DR GO; GO:0008198; F:ferrous iron binding; ISS:UniProtKB.
DR GO; GO:0031418; F:L-ascorbic acid binding; IEA:UniProtKB-KW.
DR GO; GO:0019826; F:oxygen sensor activity; ISO:RGD.
DR GO; GO:0031545; F:peptidyl-proline 4-dioxygenase activity; IDA:UniProtKB.
DR GO; GO:0031543; F:peptidyl-proline dioxygenase activity; IBA:GO_Central.
DR GO; GO:0045454; P:cell redox homeostasis; ISO:RGD.
DR GO; GO:0071456; P:cellular response to hypoxia; IBA:GO_Central.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; IDA:UniProtKB.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; ISO:RGD.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0001666; P:response to hypoxia; ISO:RGD.
DR InterPro; IPR005123; Oxoglu/Fe-dep_dioxygenase.
DR InterPro; IPR006620; Pro_4_hyd_alph.
DR InterPro; IPR044862; Pro_4_hyd_alph_FE2OG_OXY.
DR Pfam; PF13640; 2OG-FeII_Oxy_3; 1.
DR SMART; SM00702; P4Hc; 1.
DR PROSITE; PS51471; FE2OG_OXY; 1.
PE 1: Evidence at protein level;
KW Dioxygenase; Iron; Metal-binding; Nucleus; Oxidoreductase; Phosphoprotein;
KW Reference proteome; Ubl conjugation; Vitamin C.
FT CHAIN 1..415
FT /note="Prolyl hydroxylase EGLN2"
FT /id="PRO_0000415323"
FT DOMAIN 286..384
FT /note="Fe2OG dioxygenase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT REGION 1..31
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 43..89
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 108..179
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 233..243
FT /note="Beta(2)beta(3) 'finger-like' loop"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOTIF 89..134
FT /note="Bipartite nuclear localization signal"
FT /evidence="ECO:0000250|UniProtKB:Q96KS0"
FT COMPBIAS 1..23
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 52..77
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 153..168
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 305
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:Q96KS0,
FT ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 307
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:Q96KS0,
FT ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 366
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:Q96KS0,
FT ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 375
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT MOD_RES 130
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q96KS0"
SQ SEQUENCE 415 AA; 44681 MW; 2A6FE8E43254C28A CRC64;
MDSPCQPQAL NQALPQLPGS VSESLEPSRA RMGVESYLPC PLLPSYHRSG ASGEASAGNG
TPRTTATATT TTASPLREGF GGQDGGELWP LQSEGAAALV TKECQRLAAQ GARPEAPKRK
WAKDGGDAPS PSKRPWARQE NQEAKGESGV GCDSGGGSSN STTHSSGEAS SRLREEAQPS
APERLALDYI VPCMRYYGIC VKDNFLGAVL GGRVLAEVEA LKWGGRLRDG QLVSQRAIPP
RSIRGDQIAW VEGHEPGCRS IGALMAHVDA VIRHCAGRLG NYVINGRTKA MVACYPGNGL
GYVRHVDNPH GDGRCITCIY YLNQNWDVKV HGGLLQIFPE GRPVVANIEP LFDRLLIFWS
DRRNPHEVKP AYATRYAITV WYFDAKERAA ARDKYQLASG QKGVQVPVSQ PATPT
