EGLN1_MOUSE
ID EGLN1_MOUSE Reviewed; 400 AA.
AC Q91YE3; Q8VHJ2; Q922P3;
DT 16-JUN-2003, integrated into UniProtKB/Swiss-Prot.
DT 16-JUN-2003, sequence version 2.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=Egl nine homolog 1;
DE EC=1.14.11.29 {ECO:0000250|UniProtKB:Q9GZT9};
DE AltName: Full=Hypoxia-inducible factor prolyl hydroxylase 2;
DE Short=HIF-PH2;
DE Short=HIF-prolyl hydroxylase 2;
DE Short=HPH-2;
DE AltName: Full=Prolyl hydroxylase domain-containing protein 2;
DE Short=PHD2;
DE AltName: Full=SM-20;
GN Name=Egln1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 34-400.
RX PubMed=11574160; DOI=10.1016/s0378-1119(01)00633-3;
RA Taylor M.S.;
RT "Characterization and comparative analysis of the EGLN gene family.";
RL Gene 275:125-132(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 205-400, AND TISSUE SPECIFICITY.
RX PubMed=12234095; DOI=10.1139/o02-115;
RA Lieb M.E., Menzies K., Moschella M.C., Ni R., Taubman M.B.;
RT "Mammalian EGLN genes have distinct patterns of mRNA expression and
RT regulation.";
RL Biochem. Cell Biol. 80:421-426(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 268-400.
RC TISSUE=Mammary gland;
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 [5]
RP INDUCTION.
RX PubMed=10543731;
RA Moschella M.C., Menzies K., Tsao L., Lieb M.A., Kohtz J.D., Kohtz D.S.,
RA Taubman M.B.;
RT "SM-20 is a novel growth factor-responsive gene regulated during skeletal
RT muscle development and differentiation.";
RL Gene Expr. 8:59-66(1999).
RN [6]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=18096761; DOI=10.1182/blood-2007-10-117812;
RA Minamishima Y.A., Moslehi J., Bardeesy N., Cullen D., Bronson R.T.,
RA Kaelin W.G. Jr.;
RT "Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia
RT and congestive heart failure.";
RL Blood 111:3236-3244(2008).
RN [7]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=18500250; DOI=10.1038/mt.2008.90;
RA Wu S., Nishiyama N., Kano M.R., Morishita Y., Miyazono K., Itaka K.,
RA Chung U.I., Kataoka K.;
RT "Enhancement of angiogenesis through stabilization of hypoxia-inducible
RT factor-1 by silencing prolyl hydroxylase domain-2 gene.";
RL Mol. Ther. 16:1227-1234(2008).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Lung, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [9]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=21435465; DOI=10.1016/j.ajpath.2010.12.016;
RA Duan L.J., Takeda K., Fong G.H.;
RT "Prolyl hydroxylase domain protein 2 (PHD2) mediates oxygen-induced
RT retinopathy in neonatal mice.";
RL Am. J. Pathol. 178:1881-1890(2011).
CC -!- FUNCTION: Cellular oxygen sensor that catalyzes, under normoxic
CC conditions, the post-translational formation of 4-hydroxyproline in
CC hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific
CC proline found in each of the oxygen-dependent degradation (ODD) domains
CC (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates
CC HIF2A. Has a preference for the CODD site for both HIF1A and HIF1B.
CC Hydroxylated HIFs are then targeted for proteasomal degradation via the
CC von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the
CC hydroxylation reaction is attenuated allowing HIFs to escape
CC degradation resulting in their translocation to the nucleus,
CC heterodimerization with HIF1B, and increased expression of hypoxy-
CC inducible genes. EGLN1 is the most important isozyme under normoxia
CC and, through regulating the stability of HIF1, involved in various
CC hypoxia-influenced processes such as angiogenesis in retinal and
CC cardiac functionality. Target proteins are preferentially recognized
CC via a LXXLAP motif. {ECO:0000269|PubMed:18096761,
CC ECO:0000269|PubMed:18500250, ECO:0000269|PubMed:21435465}.
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:0000250|UniProtKB:Q9GZT9};
CC -!- COFACTOR:
CC Name=Fe(2+); Xref=ChEBI:CHEBI:29033;
CC Evidence={ECO:0000250|UniProtKB:Q9GZT9,
CC ECO:0000255|PROSITE-ProRule:PRU00805};
CC Note=Binds 1 Fe(2+) ion per subunit. {ECO:0000250|UniProtKB:Q9GZT9,
CC ECO:0000255|PROSITE-ProRule:PRU00805};
CC -!- COFACTOR:
CC Name=L-ascorbate; Xref=ChEBI:CHEBI:38290;
CC Evidence={ECO:0000250|UniProtKB:Q9GZT9};
CC -!- SUBUNIT: Monomer. Interacts with ING4; the interaction inhibits the
CC hydroxylation of HIF alpha proteins. Interacts with PTGES3 (via PXLE
CC motif); thereby recruiting EGLN1 to the HSP90 pathway to facilitate HIF
CC alpha proteins hydroxylation. Interacts with LIMD1. Found in a complex
CC composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with
CC EPAS1. Interacts with CBFA2T3 and HIF1A.
CC {ECO:0000250|UniProtKB:Q9GZT9}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9GZT9}. Nucleus
CC {ECO:0000250|UniProtKB:Q9GZT9}. Note=Mainly cytoplasmic. Shuttles
CC between the nucleus and cytoplasm. Nuclear export requires functional
CC XPO1. {ECO:0000250|UniProtKB:Q9GZT9}.
CC -!- TISSUE SPECIFICITY: Expressed in heart, brain liver, skeletal muscle
CC and kidney. Low levels were detected in the lung. Constitutively
CC expressed during differentiation of C2C12 skeletal myocytes.
CC {ECO:0000269|PubMed:12234095}.
CC -!- INDUCTION: Induced by growth factors in cultured vascular smooth
CC muscle. Up-regulated in proliferating myoblasts induced to form
CC differentiated myotubes. {ECO:0000269|PubMed:10543731}.
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: S-nitrosylation inhibits the enzyme activity up to 60% under
CC aerobic conditions. Chelation of Fe(2+) has no effect on the S-
CC nitrosylation. It is uncertain whether nitrosylation occurs on Cys-300
CC or Cys-303. {ECO:0000250|UniProtKB:Q9GZT9}.
CC -!- DISRUPTION PHENOTYPE: Null mice are smaller than wild type and are
CC erythematous with some animals having evidence of retroperitoneal
CC hemorrhage. The resulting polycythemia can cause thrombosis and cardiac
CC failure and animals die off after 10 weeks. Erythropoietin levels are
CC increased in kidneys but not in livers. In neonatal null mice exposed
CC to 75% oxygen, there are high levels of HIF1A nuclear abundance in
CC retinal tissues accompanied by well-preserved retinal microvessels
CC compared to wild type where oxygen-treated retinas exhibit reverse
CC effects with increased risks of retinopathy.
CC {ECO:0000269|PubMed:18096761, ECO:0000269|PubMed:18500250,
CC ECO:0000269|PubMed:21435465}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH06903.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AL672234; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AJ310546; CAC42515.1; -; mRNA.
DR EMBL; AF453878; AAL65165.1; -; mRNA.
DR EMBL; BC006903; AAH06903.1; ALT_INIT; mRNA.
DR CCDS; CCDS52706.1; -.
DR RefSeq; NP_444437.2; NM_053207.2.
DR AlphaFoldDB; Q91YE3; -.
DR SMR; Q91YE3; -.
DR BioGRID; 227481; 7.
DR STRING; 10090.ENSMUSP00000034469; -.
DR iPTMnet; Q91YE3; -.
DR PhosphoSitePlus; Q91YE3; -.
DR EPD; Q91YE3; -.
DR jPOST; Q91YE3; -.
DR MaxQB; Q91YE3; -.
DR PaxDb; Q91YE3; -.
DR PeptideAtlas; Q91YE3; -.
DR PRIDE; Q91YE3; -.
DR ProteomicsDB; 277564; -.
DR DNASU; 112405; -.
DR Ensembl; ENSMUST00000034469; ENSMUSP00000034469; ENSMUSG00000031987.
DR GeneID; 112405; -.
DR KEGG; mmu:112405; -.
DR UCSC; uc012gna.1; mouse.
DR CTD; 54583; -.
DR MGI; MGI:1932286; Egln1.
DR VEuPathDB; HostDB:ENSMUSG00000031987; -.
DR eggNOG; KOG3710; Eukaryota.
DR GeneTree; ENSGT00940000155704; -.
DR HOGENOM; CLU_022206_2_2_1; -.
DR InParanoid; Q91YE3; -.
DR OMA; YQEKANL; -.
DR OrthoDB; 1604981at2759; -.
DR PhylomeDB; Q91YE3; -.
DR TreeFam; TF314595; -.
DR BRENDA; 1.14.11.29; 3474.
DR Reactome; R-MMU-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR BioGRID-ORCS; 112405; 16 hits in 73 CRISPR screens.
DR ChiTaRS; Egln1; mouse.
DR PRO; PR:Q91YE3; -.
DR Proteomes; UP000000589; Chromosome 8.
DR RNAct; Q91YE3; protein.
DR Bgee; ENSMUSG00000031987; Expressed in myocardium of ventricle and 257 other tissues.
DR Genevisible; Q91YE3; MM.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0014069; C:postsynaptic density; IDA:SynGO.
DR GO; GO:0016706; F:2-oxoglutarate-dependent dioxygenase activity; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
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:0031545; F:peptidyl-proline 4-dioxygenase activity; ISO:MGI.
DR GO; GO:0031543; F:peptidyl-proline dioxygenase activity; ISO:MGI.
DR GO; GO:0055008; P:cardiac muscle tissue morphogenesis; IMP:MGI.
DR GO; GO:0006879; P:cellular iron ion homeostasis; IMP:ParkinsonsUK-UCL.
DR GO; GO:0071456; P:cellular response to hypoxia; IBA:GO_Central.
DR GO; GO:0060347; P:heart trabecula formation; IMP:MGI.
DR GO; GO:0060711; P:labyrinthine layer development; IMP:MGI.
DR GO; GO:1905290; P:negative regulation of CAMKK-AMPK signaling cascade; ISO:MGI.
DR GO; GO:0051344; P:negative regulation of cyclic-nucleotide phosphodiesterase activity; ISO:MGI.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; ISO:MGI.
DR GO; GO:0032364; P:oxygen homeostasis; ISO:MGI.
DR GO; GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; ISO:MGI.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR GO; GO:1901216; P:positive regulation of neuron death; ISO:MGI.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IMP:ParkinsonsUK-UCL.
DR GO; GO:0045765; P:regulation of angiogenesis; IMP:UniProtKB.
DR GO; GO:1901214; P:regulation of neuron death; IMP:ParkinsonsUK-UCL.
DR GO; GO:0099175; P:regulation of postsynapse organization; IDA:SynGO.
DR GO; GO:0099576; P:regulation of protein catabolic process at postsynapse, modulating synaptic transmission; IDA:SynGO.
DR GO; GO:0001666; P:response to hypoxia; ISO:MGI.
DR GO; GO:0071731; P:response to nitric oxide; ISS:UniProtKB.
DR GO; GO:0060412; P:ventricular septum morphogenesis; IMP:MGI.
DR InterPro; IPR005123; Oxoglu/Fe-dep_dioxygenase.
DR InterPro; IPR006620; Pro_4_hyd_alph.
DR InterPro; IPR044862; Pro_4_hyd_alph_FE2OG_OXY.
DR InterPro; IPR002893; Znf_MYND.
DR Pfam; PF13640; 2OG-FeII_Oxy_3; 1.
DR Pfam; PF01753; zf-MYND; 1.
DR SMART; SM00702; P4Hc; 1.
DR PROSITE; PS51471; FE2OG_OXY; 1.
DR PROSITE; PS01360; ZF_MYND_1; 1.
DR PROSITE; PS50865; ZF_MYND_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cytoplasm; Dioxygenase; Iron; Metal-binding; Nucleus;
KW Oxidoreductase; Phosphoprotein; Reference proteome; S-nitrosylation;
KW Vitamin C; Zinc; Zinc-finger.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT CHAIN 2..400
FT /note="Egl nine homolog 1"
FT /id="PRO_0000206662"
FT DOMAIN 271..369
FT /note="Fe2OG dioxygenase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT ZN_FING 21..58
FT /note="MYND-type; atypical"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00134"
FT REGION 6..20
FT /note="Required for nuclear export"
FT REGION 62..161
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 218..228
FT /note="Beta(2)beta(3) 'finger-like' loop"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT BINDING 21
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00134"
FT BINDING 24
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00134"
FT BINDING 33
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00134"
FT BINDING 36
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00134"
FT BINDING 42
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00134"
FT BINDING 46
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00134"
FT BINDING 54
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00134"
FT BINDING 58
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00134"
FT BINDING 290
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9,
FT ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 292
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9,
FT ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 351
FT /ligand="Fe cation"
FT /ligand_id="ChEBI:CHEBI:24875"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9,
FT ECO:0000255|PROSITE-ProRule:PRU00805"
FT BINDING 360
FT /ligand="2-oxoglutarate"
FT /ligand_id="ChEBI:CHEBI:16810"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00805"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 12
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 114
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 178
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 185
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 279
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 300
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT MOD_RES 303
FT /note="S-nitrosocysteine"
FT /evidence="ECO:0000250|UniProtKB:Q9GZT9"
FT CONFLICT 205..209
FT /note="ALHDT -> RIRHE (in Ref. 3; AAL65165)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 400 AA; 43111 MW; A7EBC2BF6E22CDB9 CRC64;
MASDSGGPGV LSASERDRQY CELCGKMENL LRCGRCRSSF YCCKEHQRQD WKKHKLVCQG
GEAPRAQPAP AQPRVAPPPG GAPGAARAGG AARRGDSAAA SRVPGPEDAA QARSGPGPAE
PGSEDPPLSR SPGPERASLC PAGGGPGEAL SPGGGLRPNG QTKPLPALKL ALEYIVPCMN
KHGICVVDDF LGRETGQQIG DEVRALHDTG KFTDGQLVSQ KSDSSKDIRG DQITWIEGKE
PGCETIGLLM SSMDDLIRHC SGKLGNYRIN GRTKAMVACY PGNGTGYVRH VDNPNGDGRC
VTCIYYLNKD WDAKVSGGIL RIFPEGKAQF ADIEPKFDRL LFFWSDRRNP HEVQPAYATR
YAITVWYFDA DERARAKVKY LTGEKGVRVE LKPNSVSKDV
