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Q91UZ4

- EGLN3_MOUSE

UniProt

Q91UZ4 - EGLN3_MOUSE

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Protein
Egl nine homolog 3
Gene
Egln3
Organism
Mus musculus (Mouse)
Status
Reviewed - 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.1 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 By similarity.
Ascorbate By similarity.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Metal bindingi135 – 1351Iron By similarity
Metal bindingi137 – 1371Iron By similarity
Metal bindingi196 – 1961Iron By similarity
Binding sitei205 – 20512-oxoglutarate By similarity

GO - Molecular functioni

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

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
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_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
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 3
PRO_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.

Protein-protein interaction databases

BioGridi227483. 3 interactions.
STRINGi10090.ENSMUSP00000041874.

Structurei

3D structure databases

ProteinModelPortaliQ91UZ4.
SMRiQ91UZ4. Positions 13-225.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini116 – 21499Fe2OG dioxygenase
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni62 – 7312Beta(2)beta(3) 'finger-like' loop By similarity
Add
BLAST
Regioni88 – 10417Required for interaction with ADRB2 By similarity
Add
BLAST

Domaini

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

Sequence similaritiesi

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.

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti65 – 651R → C in BAC32092. 1 Publication
Sequence conflicti65 – 651R → C in BAE38492. 1 Publication
Sequence conflicti65 – 651R → C in BAE41988. 1 Publication

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...

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

« 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: September 3, 2014
This is version 109 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