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Protein

Egl nine homolog 3

Gene

Egln3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript 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 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

Protein has several cofactor binding sites:
  • Fe2+PROSITE-ProRule annotationNote: Binds 1 Fe2+ ion per subunit.PROSITE-ProRule annotation
  • L-ascorbateBy 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. oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, 2-oxoglutarate as one donor, and incorporation of one atom each of oxygen into both donors Source: MGI
  4. peptidyl-proline 4-dioxygenase activity Source: MGI

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: MGI
  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
Complete GO annotation...

Keywords - Molecular functioni

Dioxygenase, Oxidoreductase

Keywords - Biological processi

Apoptosis, DNA damage

Keywords - Ligandi

Iron, Metal-binding, Vitamin C

Enzyme and pathway databases

ReactomeiREACT_276107. 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 Componenti: Chromosome 12

Organism-specific databases

MGIiMGI:1932288. Egln3.

Subcellular locationi

  1. Nucleus By similarity
  2. Cytoplasm By similarity

  3. Note: Colocalizes with WDR83 in the cytoplasm.By similarity

GO - Cellular componenti

  1. cytoplasm Source: UniProtKB
  2. nucleus Source: UniProtKB
Complete GO annotation...

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.
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

        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 IFDRLLFFWS DRRNPHEVQP
210 220 230
SYATRYAMTV WYFDAEERAE AKKKFRNLTR KTESALAKD
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. Curated

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:
EMBLi
GenBanki
DDBJi
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

GeneIDi112407.
KEGGimmu:112407.
UCSCiuc007nns.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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.

3D structure databases

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

Protein-protein interaction databases

BioGridi227483. 3 interactions.
STRINGi10090.ENSMUSP00000041874.

PTM databases

PhosphoSiteiQ91UZ4.

Proteomic databases

PRIDEiQ91UZ4.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi112407.
KEGGimmu:112407.
UCSCiuc007nns.2. mouse.

Organism-specific databases

CTDi112399.
MGIiMGI:1932288. Egln3.

Phylogenomic databases

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

Enzyme and pathway databases

ReactomeiREACT_276107. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.

Miscellaneous databases

ChiTaRSiEgln3. mouse.
NextBioi367889.
PROiQ91UZ4.
SOURCEiSearch...

Gene expression databases

BgeeiQ91UZ4.
CleanExiMM_EGLN3.
GenevestigatoriQ91UZ4.

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

« Hide 'large scale' publications
  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: April 1, 2015
This is version 115 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

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 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.