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Protein

Egl nine homolog 2

Gene

EGLN2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 HIF2A. 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. EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle. Also regulates susceptibility to normoxic oxidative neuronal death. Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation. Hydroxylates IKBKB, mediating NF-kappaB activation in hypoxic conditions. Target proteins are preferentially recognized via a LXXLAP motif.7 Publications

Catalytic activityi

Hypoxia-inducible factor-L-proline + 2-oxoglutarate + O2 = hypoxia-inducible factor-trans-4-hydroxy-L-proline + succinate + CO2.3 Publications

Cofactori

Protein has several cofactor binding sites:

Kineticsi

  1. KM=20 µM for HIF1A DLDLEMLAPYIPMDDDFQL peptide (at pH 7.5 and 37 degrees Celsius)1 Publication
  2. KM=50 µM for L-ascorbate (at pH 7.5 and 37 degrees Celsius)1 Publication
  3. KM=1.0 µM for Fe2+ (at pH 7.5 and 37 degrees Celsius)1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi297Iron; via tele nitrogenPROSITE-ProRule annotation1 PublicationImported1
    Metal bindingi299IronPROSITE-ProRule annotation1 PublicationImported1
    Metal bindingi358Iron; via tele nitrogenPROSITE-ProRule annotation1 PublicationImported1
    Binding sitei3672-oxoglutaratePROSITE-ProRule annotation1

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionDioxygenase, Oxidoreductase
    LigandIron, Metal-binding, Vitamin C

    Enzyme and pathway databases

    BioCyciMetaCyc:ENSG00000171570-MONOMER
    BRENDAi1.14.11.2 2681
    1.14.11.29 2681
    ReactomeiR-HSA-1234176 Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
    SIGNORiQ96KS0

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Egl nine homolog 2Curated (EC:1.14.11.29PROSITE-ProRule annotation3 Publications)
    Alternative name(s):
    Estrogen-induced tag 61 Publication
    Short name:
    EIT-61 Publication
    HPH-3
    Hypoxia-inducible factor prolyl hydroxylase 1
    Short name:
    HIF-PH1
    Short name:
    HIF-prolyl hydroxylase 1
    Short name:
    HPH-1
    Prolyl hydroxylase domain-containing protein 11 Publication
    Short name:
    PHD11 Publication
    Gene namesi
    Name:EGLN2Imported
    Synonyms:EIT61 Publication
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 19

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000269858.5
    HGNCiHGNC:14660 EGLN2
    MIMi606424 gene
    neXtProtiNX_Q96KS0

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi1M → A: Leads to expression of isoform p40 only. 1 Publication1
    Mutagenesisi34M → A: Leads to expression of isoform p43 only. 1 Publication1
    Mutagenesisi102K → A: Retained in the nucleus. 1 Publication1
    Mutagenesisi106R → A: Retained in the nucleus. 1 Publication1
    Mutagenesisi113R → A: Retained in the nucleus. 1 Publication1
    Mutagenesisi119R → A: Cytoplasmic and nuclear localization. Reduced transcriptional activity of HIF1A as for wild type. 1 Publication1
    Mutagenesisi134R → A: Retained in the nucleus. 1 Publication1
    Mutagenesisi297H → A: Eliminates hydroxylase activity. 1 Publication1
    Mutagenesisi299D → A: Eliminates hydroxylase activity. 1 Publication1
    Mutagenesisi358H → A: Eliminates hydroxylase activity. 2 Publications1
    Mutagenesisi367R → A: Eliminates hydroxylase activity. 1 Publication1
    Mutagenesisi367R → K: Eliminates hydroxylase activity on a HIF1A peptide. 1 Publication1

    Organism-specific databases

    DisGeNETi112398
    OpenTargetsiENSG00000269858
    PharmGKBiPA27671

    Chemistry databases

    ChEMBLiCHEMBL3028
    DrugBankiDB04847 FG-4592
    DB00126 Vitamin C
    GuidetoPHARMACOLOGYi2832

    Polymorphism and mutation databases

    BioMutaiEGLN2
    DMDMi32129513

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00002066641 – 407Egl nine homolog 2Add BLAST407

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei130PhosphoserineCombined sources1

    Keywords - PTMi

    Phosphoprotein

    Proteomic databases

    MaxQBiQ96KS0
    PaxDbiQ96KS0
    PeptideAtlasiQ96KS0
    PRIDEiQ96KS0
    ProteomicsDBi77112
    77113 [Q96KS0-2]

    PTM databases

    iPTMnetiQ96KS0
    PhosphoSitePlusiQ96KS0

    Expressioni

    Tissue specificityi

    Expressed in adult and fetal heart, brain, liver, lung, skeletal muscle, and kidney. Also expressed in testis and placenta. Highest levels in adult brain, placenta, lung, kidney, and testis. Expressed in hormone responsive tissues, including normal and cancerous mammary, ovarian and prostate epithelium.1 Publication

    Inductioni

    By estrogen. Isoform p43 is induced by hypoxia leading to protein stability. Isoform p40 repressed by hypoxia. Both isoforms are induced by proteasomal inhibitor MG132 (at protein level).4 Publications

    Gene expression databases

    BgeeiENSG00000269858 Expressed in 93 organ(s), highest expression level in testis
    CleanExiHS_EGLN2
    ExpressionAtlasiQ96KS0 baseline and differential
    GenevisibleiQ96KS0 HS

    Organism-specific databases

    HPAiHPA056649

    Interactioni

    Subunit structurei

    Interacts (preferably isoform p40) with SIAH2; the interaction targets both SIAH2 isoforms for proteasomal degradation in vitro. Interacts with LIMD1, WTIP and AJUBA.2 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    HIF1AQ166652EBI-726614,EBI-447269

    Protein-protein interaction databases

    BioGridi125184, 26 interactors
    IntActiQ96KS0, 7 interactors
    MINTiQ96KS0
    STRINGi9606.ENSP00000307080

    Chemistry databases

    BindingDBiQ96KS0

    Structurei

    Secondary structure

    1407
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliQ96KS0
    SMRiQ96KS0
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini278 – 376Fe2OG dioxygenasePROSITE-ProRule annotationAdd BLAST99

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni225 – 235Beta(2)beta(3) 'finger-like' loopBy similarityAdd BLAST11

    Motif

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Motifi89 – 134Bipartite nuclear localization signal1 PublicationAdd BLAST46

    Domaini

    The Beta2beta3 'finger-like' loop domain is important for substrate (HIFs' CODD/NODD) selectivity.By similarity

    Phylogenomic databases

    eggNOGiKOG3710 Eukaryota
    ENOG410ZHZN LUCA
    GeneTreeiENSGT00390000001936
    HOGENOMiHOG000013099
    HOVERGENiHBG051456
    InParanoidiQ96KS0
    KOiK09592
    OMAiQDGGELW
    OrthoDBiEOG091G03SP
    PhylomeDBiQ96KS0
    TreeFamiTF314595

    Family and domain databases

    InterProiView protein in InterPro
    IPR005123 Oxoglu/Fe-dep_dioxygenase
    IPR006620 Pro_4_hyd_alph
    PfamiView protein in Pfam
    PF13640 2OG-FeII_Oxy_3, 1 hit
    SMARTiView protein in SMART
    SM00702 P4Hc, 1 hit
    PROSITEiView protein in PROSITE
    PS51471 FE2OG_OXY, 1 hit

    Sequences (2+)i

    Sequence statusi: Complete.

    This entry describes 2 isoformsi produced by alternative initiation. AlignAdd to basket

    This entry has 2 described isoforms and 11 potential isoforms that are computationally mapped.Show allAlign All

    Isoform p43 (identifier: Q96KS0-1) [UniParc]FASTAAdd to basket
    Also known as: PHD1p43

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide
            10         20         30         40         50
    MDSPCQPQPL SQALPQLPGS SSEPLEPEPG RARMGVESYL PCPLLPSYHC
    60 70 80 90 100
    PGVPSEASAG SGTPRATATS TTASPLRDGF GGQDGGELRP LQSEGAAALV
    110 120 130 140 150
    TKGCQRLAAQ GARPEAPKRK WAEDGGDAPS PSKRPWARQE NQEAEREGGM
    160 170 180 190 200
    SCSCSSGSGE ASAGLMEEAL PSAPERLALD YIVPCMRYYG ICVKDSFLGA
    210 220 230 240 250
    ALGGRVLAEV EALKRGGRLR DGQLVSQRAI PPRSIRGDQI AWVEGHEPGC
    260 270 280 290 300
    RSIGALMAHV DAVIRHCAGR LGSYVINGRT KAMVACYPGN GLGYVRHVDN
    310 320 330 340 350
    PHGDGRCITC IYYLNQNWDV KVHGGLLQIF PEGRPVVANI EPLFDRLLIF
    360 370 380 390 400
    WSDRRNPHEV KPAYATRYAI TVWYFDAKER AAAKDKYQLA SGQKGVQVPV

    SQPPTPT
    Length:407
    Mass (Da):43,650
    Last modified:December 1, 2001 - v1
    Checksum:iF172E9B0482C9CF3
    GO
    Isoform p40 (identifier: Q96KS0-2) [UniParc]FASTAAdd to basket
    Also known as: PHD1p40

    The sequence of this isoform differs from the canonical sequence as follows:
         1-33: Missing.

    Show »
    Length:374
    Mass (Da):40,168
    Checksum:i228015782B7DE743
    GO

    Computationally mapped potential isoform sequencesi

    There are 11 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    A0A0C4DGR4A0A0C4DGR4_HUMAN
    Egl nine homolog 2
    EGLN2
    125Annotation score:
    M0R0Z6M0R0Z6_HUMAN
    Egl nine homolog 2
    EGLN2
    139Annotation score:
    M0QXM8M0QXM8_HUMAN
    Egl nine homolog 2
    EGLN2
    77Annotation score:
    M0QXR0M0QXR0_HUMAN
    Egl nine homolog 2
    EGLN2
    94Annotation score:
    M0R110M0R110_HUMAN
    Egl nine homolog 2
    EGLN2
    101Annotation score:
    M0R1W4M0R1W4_HUMAN
    Egl nine homolog 2
    EGLN2
    72Annotation score:
    M0R035M0R035_HUMAN
    Egl nine homolog 2
    EGLN2
    87Annotation score:
    M0R1L0M0R1L0_HUMAN
    Egl nine homolog 2
    EGLN2
    96Annotation score:
    M0R350M0R350_HUMAN
    Egl nine homolog 2
    EGLN2
    128Annotation score:
    M0R1A3M0R1A3_HUMAN
    Egl nine homolog 2
    EGLN2
    51Annotation score:
    There is more potential isoformShow all

    Sequence cautioni

    The sequence AAH01723 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti176R → P in AAK82943 (PubMed:11850811).Curated1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0388361 – 33Missing in isoform p40. CuratedAdd BLAST33

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AJ310544 mRNA Translation: CAC42510.1
    AY040565 mRNA Translation: AAK82943.1
    AK291385 mRNA Translation: BAF84074.1
    AL832506 mRNA No translation available.
    AC008537 Genomic DNA No translation available.
    CH471126 Genomic DNA Translation: EAW57008.1
    BC001723 mRNA Translation: AAH01723.1 Different initiation.
    BC036051 mRNA Translation: AAH36051.1
    CCDSiCCDS12567.1 [Q96KS0-1]
    RefSeqiNP_444274.1, NM_053046.3 [Q96KS0-1]
    NP_542770.2, NM_080732.3 [Q96KS0-1]
    UniGeneiHs.515417
    Hs.631539
    Hs.730737

    Genome annotation databases

    EnsembliENST00000303961; ENSP00000307080; ENSG00000269858 [Q96KS0-1]
    ENST00000406058; ENSP00000385253; ENSG00000269858 [Q96KS0-1]
    ENST00000593726; ENSP00000469686; ENSG00000269858 [Q96KS0-1]
    GeneIDi112398
    KEGGihsa:112398
    UCSCiuc002opg.5 human [Q96KS0-1]

    Keywords - Coding sequence diversityi

    Alternative initiation

    Similar proteinsi

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AJ310544 mRNA Translation: CAC42510.1
    AY040565 mRNA Translation: AAK82943.1
    AK291385 mRNA Translation: BAF84074.1
    AL832506 mRNA No translation available.
    AC008537 Genomic DNA No translation available.
    CH471126 Genomic DNA Translation: EAW57008.1
    BC001723 mRNA Translation: AAH01723.1 Different initiation.
    BC036051 mRNA Translation: AAH36051.1
    CCDSiCCDS12567.1 [Q96KS0-1]
    RefSeqiNP_444274.1, NM_053046.3 [Q96KS0-1]
    NP_542770.2, NM_080732.3 [Q96KS0-1]
    UniGeneiHs.515417
    Hs.631539
    Hs.730737

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    5V1BX-ray2.49A167-403[»]
    ProteinModelPortaliQ96KS0
    SMRiQ96KS0
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi125184, 26 interactors
    IntActiQ96KS0, 7 interactors
    MINTiQ96KS0
    STRINGi9606.ENSP00000307080

    Chemistry databases

    BindingDBiQ96KS0
    ChEMBLiCHEMBL3028
    DrugBankiDB04847 FG-4592
    DB00126 Vitamin C
    GuidetoPHARMACOLOGYi2832

    PTM databases

    iPTMnetiQ96KS0
    PhosphoSitePlusiQ96KS0

    Polymorphism and mutation databases

    BioMutaiEGLN2
    DMDMi32129513

    Proteomic databases

    MaxQBiQ96KS0
    PaxDbiQ96KS0
    PeptideAtlasiQ96KS0
    PRIDEiQ96KS0
    ProteomicsDBi77112
    77113 [Q96KS0-2]

    Protocols and materials databases

    DNASUi112398
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000303961; ENSP00000307080; ENSG00000269858 [Q96KS0-1]
    ENST00000406058; ENSP00000385253; ENSG00000269858 [Q96KS0-1]
    ENST00000593726; ENSP00000469686; ENSG00000269858 [Q96KS0-1]
    GeneIDi112398
    KEGGihsa:112398
    UCSCiuc002opg.5 human [Q96KS0-1]

    Organism-specific databases

    CTDi112398
    DisGeNETi112398
    EuPathDBiHostDB:ENSG00000269858.5
    GeneCardsiEGLN2
    HGNCiHGNC:14660 EGLN2
    HPAiHPA056649
    MIMi606424 gene
    neXtProtiNX_Q96KS0
    OpenTargetsiENSG00000269858
    PharmGKBiPA27671
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG3710 Eukaryota
    ENOG410ZHZN LUCA
    GeneTreeiENSGT00390000001936
    HOGENOMiHOG000013099
    HOVERGENiHBG051456
    InParanoidiQ96KS0
    KOiK09592
    OMAiQDGGELW
    OrthoDBiEOG091G03SP
    PhylomeDBiQ96KS0
    TreeFamiTF314595

    Enzyme and pathway databases

    BioCyciMetaCyc:ENSG00000171570-MONOMER
    BRENDAi1.14.11.2 2681
    1.14.11.29 2681
    ReactomeiR-HSA-1234176 Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
    SIGNORiQ96KS0

    Miscellaneous databases

    ChiTaRSiEGLN2 human
    GeneWikiiEGLN2
    GenomeRNAii112398
    PROiPR:Q96KS0
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000269858 Expressed in 93 organ(s), highest expression level in testis
    CleanExiHS_EGLN2
    ExpressionAtlasiQ96KS0 baseline and differential
    GenevisibleiQ96KS0 HS

    Family and domain databases

    InterProiView protein in InterPro
    IPR005123 Oxoglu/Fe-dep_dioxygenase
    IPR006620 Pro_4_hyd_alph
    PfamiView protein in Pfam
    PF13640 2OG-FeII_Oxy_3, 1 hit
    SMARTiView protein in SMART
    SM00702 P4Hc, 1 hit
    PROSITEiView protein in PROSITE
    PS51471 FE2OG_OXY, 1 hit
    ProtoNetiSearch...

    Entry informationi

    Entry nameiEGLN2_HUMAN
    AccessioniPrimary (citable) accession number: Q96KS0
    Secondary accession number(s): A8K5S0, Q8WWY4, Q9BV14
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 16, 2003
    Last sequence update: December 1, 2001
    Last modified: November 7, 2018
    This is version 160 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    2. Human chromosome 19
      Human chromosome 19: entries, gene names and cross-references to MIM
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
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