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Q91UZ4

- EGLN3_MOUSE

UniProt

Q91UZ4 - EGLN3_MOUSE

Protein

Egl nine homolog 3

Gene

Egln3

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at transcript leveli
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    • History
      Entry version 110 (01 Oct 2014)
      Sequence version 1 (01 Dec 2001)
      Previous versions | rss
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    Functioni

    Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway By similarity. 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. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. 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. ELGN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Target proteins are preferencially recognized via a LXXLAP motif.By similarity1 Publication

    Catalytic activityi

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

    Cofactori

    Binds 1 Fe2+ ion per subunit.PROSITE-ProRule annotation
    Ascorbate.By similarity

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Metal bindingi135 – 1351IronPROSITE-ProRule annotation
    Metal bindingi137 – 1371IronPROSITE-ProRule annotation
    Metal bindingi196 – 1961IronPROSITE-ProRule annotation
    Binding sitei205 – 20512-oxoglutaratePROSITE-ProRule annotation

    GO - Molecular functioni

    1. iron ion binding Source: InterPro
    2. L-ascorbic acid binding Source: UniProtKB-KW
    3. peptidyl-proline 4-dioxygenase activity Source: Ensembl

    GO - Biological processi

    1. activation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
    2. apoptotic process Source: UniProtKB
    3. cellular response to DNA damage stimulus Source: UniProtKB-KW
    4. peptidyl-proline hydroxylation to 4-hydroxy-L-proline Source: Ensembl
    5. protein hydroxylation Source: UniProtKB
    6. regulation of cell proliferation Source: UniProtKB
    7. regulation of neuron apoptotic process Source: UniProtKB
    8. response to hypoxia Source: Ensembl

    Keywords - Molecular functioni

    Dioxygenase, Oxidoreductase

    Keywords - Biological processi

    Apoptosis, DNA damage

    Keywords - Ligandi

    Iron, Metal-binding, Vitamin C

    Enzyme and pathway databases

    ReactomeiREACT_199108. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Egl nine homolog 3 (EC:1.14.11.29)
    Alternative name(s):
    Hypoxia-inducible factor prolyl hydroxylase 3
    Short name:
    HIF-PH3
    Short name:
    HIF-prolyl hydroxylase 3
    Short name:
    HPH-3
    Prolyl hydroxylase domain-containing protein 3
    Short name:
    PHD3
    SM-20
    Gene namesi
    Name:Egln3
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 12

    Organism-specific databases

    MGIiMGI:1932288. Egln3.

    Subcellular locationi

    Nucleus By similarity. Cytoplasm By similarity
    Note: Colocalizes with WDR83 in the cytoplasm.By similarity

    GO - Cellular componenti

    1. cytoplasm Source: UniProtKB
    2. nucleus Source: UniProtKB

    Keywords - Cellular componenti

    Cytoplasm, Nucleus

    Pathology & Biotechi

    Disruption phenotypei

    Null mice exhibit reduced apoptosis of in sympathetic neurons. However, the sympathoadrenal system appears hypofunctional with reduced target tissue innervation, adrenal medullary secretory capacity, sympathoadrenal responses, and systemic blood pressure. There is an increase in ADRB2 abundance and decrease of ADRB1 abundance in heart.3 Publications

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 239239Egl nine homolog 3PRO_0000206667Add
    BLAST

    Proteomic databases

    PRIDEiQ91UZ4.

    PTM databases

    PhosphoSiteiQ91UZ4.

    Expressioni

    Tissue specificityi

    Highly expressed in cardiac and smooth muscle. Also high expression in brain, skeletal muscle and kidney. Low levels in lung.1 Publication

    Developmental stagei

    Detected at E8.5 in proliferating myoblasts of the dermomyotome and the developing heart tube. From dermomyotomal cells of the rostral somites expression progressed in a rostral to caudal pattern, with highest levels seen in the muscle primordia and mature muscles.1 Publication

    Inductioni

    Induced by hypoxia. Up-regulated in proliferating myoblasts induced to form differentiated myotubes.1 Publication

    Gene expression databases

    BgeeiQ91UZ4.
    CleanExiMM_EGLN3.
    GenevestigatoriQ91UZ4.

    Interactioni

    Subunit structurei

    Interacts with ADRB2; the interaction hydroxylates ADRB2 facilitating its ubiquitination by the VHL-E3 ligase complex. Interacts with PKM; the interaction hydroxylates PKM in hypoxia. Interacts with WDR83; the interaction leads to almost complete elimination of HIF-mediated reporter activity By similarity. Interacts with BCL2 (via its BH4 domain); the interaction disrupts the BAX-BCL4 complex inhibiting the anti-apoptotic activity of BCL2. Interacts with LIMD1, WTIP and AJUBA By similarity.By similarity

    Protein-protein interaction databases

    BioGridi227483. 3 interactions.
    STRINGi10090.ENSMUSP00000041874.

    Structurei

    3D structure databases

    ProteinModelPortaliQ91UZ4.
    SMRiQ91UZ4. Positions 13-225.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini116 – 21499Fe2OG dioxygenasePROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni62 – 7312Beta(2)beta(3) 'finger-like' loopBy similarityAdd
    BLAST
    Regioni88 – 10417Required for interaction with ADRB2By similarityAdd
    BLAST

    Domaini

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

    Sequence similaritiesi

    Contains 1 Fe2OG dioxygenase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiNOG326511.
    GeneTreeiENSGT00390000001936.
    HOGENOMiHOG000004818.
    HOVERGENiHBG051455.
    InParanoidiQ91UZ4.
    KOiK09592.
    OrthoDBiEOG7TBC2W.
    PhylomeDBiQ91UZ4.
    TreeFamiTF314595.

    Family and domain databases

    InterProiIPR005123. Oxoglu/Fe-dep_dioxygenase.
    IPR006620. Pro_4_hyd_alph.
    [Graphical view]
    PfamiPF13640. 2OG-FeII_Oxy_3. 1 hit.
    [Graphical view]
    SMARTiSM00702. P4Hc. 1 hit.
    [Graphical view]
    PROSITEiPS51471. FE2OG_OXY. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q91UZ4-1 [UniParc]FASTAAdd to Basket

    « Hide

    MPLGHIMRLD LEKIALEYIV PCLHEVGFCY LDNFLGEVVG DCVLERVKQL    50
    HYNGALRDGQ LAGPRAGVSK RHLRGDQITW IGGNEEGCEA INFLLSLIDR 100
    LVLYCGSRLG KYYVKERSKA MVACYPGNGT GYVRHVDNPN GDGRCITCIY 150
    YLNKNWDAKL HGGVLRIFPE GKSFVADVEP IFDRLLFFWS DRRNPHEVQP 200
    SYATRYAMTV WYFDAEERAE AKKKFRNLTR KTESALAKD 239
    Length:239
    Mass (Da):27,302
    Last modified:December 1, 2001 - v1
    Checksum:iF4102753C6498DE5
    GO

    Sequence cautioni

    The sequence AAH22961.1 differs from that shown. Reason: Erroneous initiation.

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti65 – 651R → C in BAC32092. (PubMed:16141072)Curated
    Sequence conflicti65 – 651R → C in BAE38492. (PubMed:16141072)Curated
    Sequence conflicti65 – 651R → C in BAE41988. (PubMed:16141072)Curated

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF421882 mRNA. Translation: AAL17824.1.
    AJ310548 mRNA. Translation: CAC42517.1.
    AK044787 mRNA. Translation: BAC32092.1.
    AK165972 mRNA. Translation: BAE38492.1.
    AK170732 mRNA. Translation: BAE41988.1.
    BC022961 mRNA. Translation: AAH22961.1. Different initiation.
    BC044926 mRNA. Translation: AAH44926.1.
    BC058278 mRNA. Translation: AAH58278.1.
    BC069893 mRNA. Translation: AAH69893.1.
    CCDSiCCDS25908.1.
    RefSeqiNP_082409.2. NM_028133.2.
    UniGeneiMm.133037.

    Genome annotation databases

    EnsembliENSMUST00000039516; ENSMUSP00000041874; ENSMUSG00000035105.
    GeneIDi112407.
    KEGGimmu:112407.
    UCSCiuc007nns.2. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    AF421882 mRNA. Translation: AAL17824.1 .
    AJ310548 mRNA. Translation: CAC42517.1 .
    AK044787 mRNA. Translation: BAC32092.1 .
    AK165972 mRNA. Translation: BAE38492.1 .
    AK170732 mRNA. Translation: BAE41988.1 .
    BC022961 mRNA. Translation: AAH22961.1 . Different initiation.
    BC044926 mRNA. Translation: AAH44926.1 .
    BC058278 mRNA. Translation: AAH58278.1 .
    BC069893 mRNA. Translation: AAH69893.1 .
    CCDSi CCDS25908.1.
    RefSeqi NP_082409.2. NM_028133.2.
    UniGenei Mm.133037.

    3D structure databases

    ProteinModelPortali Q91UZ4.
    SMRi Q91UZ4. Positions 13-225.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 227483. 3 interactions.
    STRINGi 10090.ENSMUSP00000041874.

    PTM databases

    PhosphoSitei Q91UZ4.

    Proteomic databases

    PRIDEi Q91UZ4.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000039516 ; ENSMUSP00000041874 ; ENSMUSG00000035105 .
    GeneIDi 112407.
    KEGGi mmu:112407.
    UCSCi uc007nns.2. mouse.

    Organism-specific databases

    CTDi 112399.
    MGIi MGI:1932288. Egln3.

    Phylogenomic databases

    eggNOGi NOG326511.
    GeneTreei ENSGT00390000001936.
    HOGENOMi HOG000004818.
    HOVERGENi HBG051455.
    InParanoidi Q91UZ4.
    KOi K09592.
    OrthoDBi EOG7TBC2W.
    PhylomeDBi Q91UZ4.
    TreeFami TF314595.

    Enzyme and pathway databases

    Reactomei REACT_199108. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.

    Miscellaneous databases

    ChiTaRSi EGLN3. mouse.
    NextBioi 367889.
    PROi Q91UZ4.
    SOURCEi Search...

    Gene expression databases

    Bgeei Q91UZ4.
    CleanExi MM_EGLN3.
    Genevestigatori Q91UZ4.

    Family and domain databases

    InterProi IPR005123. Oxoglu/Fe-dep_dioxygenase.
    IPR006620. Pro_4_hyd_alph.
    [Graphical view ]
    Pfami PF13640. 2OG-FeII_Oxy_3. 1 hit.
    [Graphical view ]
    SMARTi SM00702. P4Hc. 1 hit.
    [Graphical view ]
    PROSITEi PS51471. FE2OG_OXY. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "SM-20 is a novel growth factor-responsive gene regulated during skeletal muscle development and differentiation."
      Moschella M.C., Menzies K., Tsao L., Lieb M.A., Kohtz J.D., Kohtz D.S., Taubman M.B.
      Gene Expr. 8:59-66(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], DEVELOPMENTAL STAGE.
      Tissue: Embryo.
    2. "Characterization and comparative analysis of the EGLN gene family."
      Taylor M.S.
      Gene 275:125-132(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    3. "The transcriptional landscape of the mammalian genome."
      Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
      , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
      Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Strain: C57BL/6J and NOD.
      Tissue: Dendritic cell, Lung and Retina.
    4. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Strain: FVB/N-3 and NMRI.
      Tissue: Mammary gland.
    5. "Mammalian EGLN genes have distinct patterns of mRNA expression and regulation."
      Lieb M.E., Menzies K., Moschella M.C., Ni R., Taubman M.B.
      Biochem. Cell Biol. 80:421-426(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY.
    6. Cited for: DISRUPTION PHENOTYPE.
    7. "A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo."
      Minamishima Y.A., Moslehi J., Padera R.F., Bronson R.T., Liao R., Kaelin W.G. Jr.
      Mol. Cell. Biol. 29:5729-5741(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE.
    8. "Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL."
      Xie L., Xiao K., Whalen E.J., Forrester M.T., Freeman R.S., Fong G., Gygi S.P., Lefkowitz R.J., Stamler J.S.
      Sci. Signal. 2:RA33-RA33(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE.
    9. Cited for: FUNCTION, INDUCTION.

    Entry informationi

    Entry nameiEGLN3_MOUSE
    AccessioniPrimary (citable) accession number: Q91UZ4
    Secondary accession number(s): Q3TCG8
    , Q8C8M6, Q8CCA8, Q8R5C7
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: June 16, 2003
    Last sequence update: December 1, 2001
    Last modified: October 1, 2014
    This is version 110 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3