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Protein

Egl nine homolog 3

Gene

Egln3

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

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 neurones, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Target proteins are preferentially recognized via a LXXLAP motif.By similarity4 Publications

Catalytic activityi

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

Cofactori

Protein has several cofactor binding sites:

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

  • iron ion binding Source: InterPro
  • L-ascorbic acid binding Source: UniProtKB-KW
  • peptidyl-proline dioxygenase activity Source: RGD

GO - Biological processi

  • activation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • apoptotic process Source: UniProtKB
  • cellular response to DNA damage stimulus Source: UniProtKB-KW
  • peptidyl-proline hydroxylation Source: GOC
  • regulation of cell proliferation Source: RGD
  • regulation of neuron apoptotic process Source: UniProtKB
  • response to hypoxia Source: RGD
Complete GO annotation...

Keywords - Molecular functioni

Dioxygenase, Oxidoreductase

Keywords - Biological processi

Apoptosis, DNA damage

Keywords - Ligandi

Iron, Metal-binding, Vitamin C

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
Synonyms:Sm20
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi71019. Egln3.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: RGD
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 239239Egl nine homolog 3PRO_0000022730Add
BLAST

Proteomic databases

PaxDbiQ62630.

PTM databases

PhosphoSiteiQ62630.

Expressioni

Tissue specificityi

Highly expressed in vascular smooth muscle. Moderately expressed in esophagus, stomach, small bowel and aorta. Low levels in tail and kidney. Expression also in pheochromocytoma cell line PC-12.4 Publications

Inductioni

By PDGF and angiotensin II in aortic smooth muscle cells. By deprivation of NGF in neuronal cell cultures. Induced during coronary heart ligation.4 Publications

Interactioni

Subunit structurei

Interacts with ADRB2; the interaction hydroxylates ADRB2 facilitating its ubiquitination by the VHL-E3 ligase complex. Interacts with PAX2; the interaction targets PAX2 for destruction. Interacts with PKM; the interaction hydroxylates PKM in hypoxia (By similarity). Interacts with WDR83; the interaction leads to almost complete elimination of HIF-mediated reporter activity. 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

BioGridi248549. 1 interaction.
STRINGi10116.ENSRNOP00000007219.

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

eggNOGiKOG3710. Eukaryota.
ENOG410ZHZN. LUCA.
HOGENOMiHOG000004818.
HOVERGENiHBG051455.
InParanoidiQ62630.
KOiK09592.

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.

Q62630-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MPLGHIMRLD LEKIALEYIV PCLHEVGFCY LDNFLGEVVG DCVLERVKQL
60 70 80 90 100
HYNGALRDGQ LAGPRAGVSK RHLRGDQITW IGGNEEGCEA INFLLSLIDR
110 120 130 140 150
LVLYCGSRLG KYYVKERSKA MVACYPGNGT GYVRHVDNPN GDGRCITCIY
160 170 180 190 200
YLNKNWDAKL HGGVLRIFPE GKSFVADVEP IFDRLLFSWS DRRNPHEVQP
210 220 230
SYATRYAMTV WYFDAEERAE AKKKFRNLTR KTESALAKD
Length:239
Mass (Da):27,242
Last modified:January 25, 2012 - v2
Checksum:iF410274976499755
GO

Sequence cautioni

The sequence AAA19321.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U06713 mRNA. Translation: AAA19321.1. Different initiation.
PIRiA53770.
RefSeqiNP_062244.1. NM_019371.1.
UniGeneiRn.10994.

Genome annotation databases

GeneIDi54702.
KEGGirno:54702.
UCSCiRGD:71019. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U06713 mRNA. Translation: AAA19321.1. Different initiation.
PIRiA53770.
RefSeqiNP_062244.1. NM_019371.1.
UniGeneiRn.10994.

3D structure databases

ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi248549. 1 interaction.
STRINGi10116.ENSRNOP00000007219.

PTM databases

PhosphoSiteiQ62630.

Proteomic databases

PaxDbiQ62630.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi54702.
KEGGirno:54702.
UCSCiRGD:71019. rat.

Organism-specific databases

CTDi112399.
RGDi71019. Egln3.

Phylogenomic databases

eggNOGiKOG3710. Eukaryota.
ENOG410ZHZN. LUCA.
HOGENOMiHOG000004818.
HOVERGENiHBG051455.
InParanoidiQ62630.
KOiK09592.

Miscellaneous databases

NextBioi611059.
PROiQ62630.

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]
ProtoNetiSearch...

Publicationsi

  1. "Identification of a novel growth factor-responsive gene in vascular smooth muscle cells."
    Wax S.D., Rosenfield C.L., Taubman M.B.
    J. Biol. Chem. 269:13041-13047(1994) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, INDUCTION.
    Strain: Sprague-Dawley.
    Tissue: Aortic smooth muscle.
  2. "Expression of the SM-20 gene promotes death in nerve growth factor-dependent sympathetic neurons."
    Lipscomb E.A., Sarmiere P.D., Crowder R.J., Freeman R.S.
    J. Neurochem. 73:429-432(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, INDUCTION.
  3. Cited for: FUNCTION.
  4. "SM-20 is a novel mitochondrial protein that causes caspase-dependent cell death in nerve growth factor-dependent neurons."
    Lipscomb E.A., Sarmiere P.D., Freeman R.S.
    J. Biol. Chem. 276:5085-5092(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, SUBCELLULAR LOCATION.
  5. "Regulation of the SM-20 prolyl hydroxylase gene in smooth muscle cells."
    Menzies K., Liu B., Kim W.J., Moschella M.C., Taubman M.B.
    Biochem. Biophys. Res. Commun. 317:801-810(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: IDENTIFICATION OF INITIATION SITE, INDUCTION, TISSUE SPECIFICITY.
  6. "The novel WD-repeat protein Morg1 acts as a molecular scaffold for hypoxia-inducible factor prolyl hydroxylase 3 (PHD3)."
    Hopfer U., Hopfer H., Jablonski K., Stahl R.A.K., Wolf G.
    J. Biol. Chem. 281:8645-8655(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH WDR83, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
  7. "HIF prolyl hydroxylases in the rat; organ distribution and changes in expression following hypoxia and coronary artery ligation."
    Willam C., Maxwell P.H., Nichols L., Lygate C., Tian Y.M., Bernhardt W., Wiesener M., Ratcliffe P.J., Eckardt K.U., Pugh C.W.
    J. Mol. Cell. Cardiol. 41:68-77(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION, INDUCTION.
  8. "Prolyl hydroxylase 3 interacts with Bcl-2 to regulate doxorubicin-induced apoptosis in H9c2 cells."
    Liu Y., Huo Z., Yan B., Lin X., Zhou Z.N., Liang X., Zhu W., Liang D., Li L., Liu Y., Zhao H., Sun Y., Chen Y.H.
    Biochem. Biophys. Res. Commun. 401:231-237(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH BCL2, FUNCTION.

Entry informationi

Entry nameiEGLN3_RAT
AccessioniPrimary (citable) accession number: Q62630
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 16, 2003
Last sequence update: January 25, 2012
Last modified: November 11, 2015
This is version 109 of the entry and version 2 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. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.