Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

Q91UZ4 (EGLN3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 108. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:Egln3
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length239 AA.
Sequence statusComplete.
Protein existenceEvidence at transcript level

General annotation (Comments)

Function

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. Ref.9

Catalytic activity

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

Cofactor

Binds 1 Fe2+ ion per subunit By similarity.

Ascorbate By similarity.

Subunit structure

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.

Subcellular location

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

Tissue specificity

Highly expressed in cardiac and smooth muscle. Also high expression in brain, skeletal muscle and kidney. Low levels in lung. Ref.5

Developmental stage

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. Ref.1

Induction

Induced by hypoxia. Up-regulated in proliferating myoblasts induced to form differentiated myotubes. Ref.9

Domain

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

Disruption phenotype

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. Ref.6 Ref.7 Ref.8

Sequence similarities

Contains 1 Fe2OG dioxygenase domain.

Sequence caution

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

Ontologies

Keywords
   Biological processApoptosis
DNA damage
   Cellular componentCytoplasm
Nucleus
   LigandIron
Metal-binding
Vitamin C
   Molecular functionDioxygenase
Oxidoreductase
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of cysteine-type endopeptidase activity involved in apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to DNA damage stimulus

Inferred from electronic annotation. Source: UniProtKB-KW

peptidyl-proline hydroxylation to 4-hydroxy-L-proline

Inferred from electronic annotation. Source: Ensembl

protein hydroxylation

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of cell proliferation

Inferred from mutant phenotype Ref.6. Source: UniProtKB

regulation of neuron apoptotic process

Inferred from mutant phenotype Ref.6. Source: UniProtKB

response to hypoxia

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcytoplasm

Inferred from sequence or structural similarity. Source: UniProtKB

nucleus

Inferred from sequence or structural similarity. Source: UniProtKB

   Molecular_functionL-ascorbic acid binding

Inferred from electronic annotation. Source: UniProtKB-KW

iron ion binding

Inferred from electronic annotation. Source: InterPro

peptidyl-proline 4-dioxygenase activity

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 239239Egl nine homolog 3
PRO_0000206667

Regions

Domain116 – 21499Fe2OG dioxygenase
Region62 – 7312Beta(2)beta(3) 'finger-like' loop By similarity
Region88 – 10417Required for interaction with ADRB2 By similarity

Sites

Metal binding1351Iron By similarity
Metal binding1371Iron By similarity
Metal binding1961Iron By similarity
Binding site20512-oxoglutarate By similarity

Experimental info

Sequence conflict651R → C in BAC32092. Ref.3
Sequence conflict651R → C in BAE38492. Ref.3
Sequence conflict651R → C in BAE41988. Ref.3

Sequences

Sequence LengthMass (Da)Tools
Q91UZ4 [UniParc].

Last modified December 1, 2001. Version 1.
Checksum: F4102753C6498DE5

FASTA23927,302
        10         20         30         40         50         60 
MPLGHIMRLD LEKIALEYIV PCLHEVGFCY LDNFLGEVVG DCVLERVKQL HYNGALRDGQ 

        70         80         90        100        110        120 
LAGPRAGVSK RHLRGDQITW IGGNEEGCEA INFLLSLIDR LVLYCGSRLG KYYVKERSKA 

       130        140        150        160        170        180 
MVACYPGNGT GYVRHVDNPN GDGRCITCIY YLNKNWDAKL HGGVLRIFPE GKSFVADVEP 

       190        200        210        220        230 
IFDRLLFFWS DRRNPHEVQP SYATRYAMTV WYFDAEERAE AKKKFRNLTR KTESALAKD 

« Hide

References

« Hide 'large scale' references
[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. expand/collapse author list , 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]"Abnormal sympathoadrenal development and systemic hypotension in PHD3-/-mice."
Bishop T., Gallagher D., Pascual A., Lygate C.A., de Bono J.P., Nicholls L.G., Ortega-Saenz P., Oster H., Wijeyekoon B., Sutherland A.I., Grosfeld A., Aragones J., Schneider M., van Geyte K., Teixeira D., Diez-Juan A., Lopez-Barneo J., Channon K.M. expand/collapse author list , Maxwell P.H., Pugh C.W., Davies A.M., Carmeliet P., Ratcliffe P.J.
Mol. Cell. Biol. 28:3386-3400(2008) [PubMed] [Europe PMC] [Abstract]
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]"Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice."
Walmsley S.R., Chilvers E.R., Thompson A.A., Vaughan K., Marriott H.M., Parker L.C., Shaw G., Parmar S., Schneider M., Sabroe I., Dockrell D.H., Milo M., Taylor C.T., Johnson R.S., Pugh C.W., Ratcliffe P.J., Maxwell P.H., Carmeliet P., Whyte M.K.
J. Clin. Invest. 121:1053-1063(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS25908.1.
RefSeqNP_082409.2. NM_028133.2.
UniGeneMm.133037.

3D structure databases

ProteinModelPortalQ91UZ4.
SMRQ91UZ4. Positions 13-225.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid227483. 3 interactions.
STRING10090.ENSMUSP00000041874.

PTM databases

PhosphoSiteQ91UZ4.

Proteomic databases

PRIDEQ91UZ4.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000039516; ENSMUSP00000041874; ENSMUSG00000035105.
GeneID112407.
KEGGmmu:112407.
UCSCuc007nns.2. mouse.

Organism-specific databases

CTD112399.
MGIMGI:1932288. Egln3.

Phylogenomic databases

eggNOGNOG326511.
GeneTreeENSGT00390000001936.
HOGENOMHOG000004818.
HOVERGENHBG051455.
InParanoidQ91UZ4.
KOK09592.
OrthoDBEOG7TBC2W.
PhylomeDBQ91UZ4.
TreeFamTF314595.

Gene expression databases

BgeeQ91UZ4.
CleanExMM_EGLN3.
GenevestigatorQ91UZ4.

Family and domain databases

InterProIPR005123. Oxoglu/Fe-dep_dioxygenase.
IPR006620. Pro_4_hyd_alph.
[Graphical view]
PfamPF13640. 2OG-FeII_Oxy_3. 1 hit.
[Graphical view]
SMARTSM00702. P4Hc. 1 hit.
[Graphical view]
PROSITEPS51471. FE2OG_OXY. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSEGLN3. mouse.
NextBio367889.
PROQ91UZ4.
SOURCESearch...

Entry information

Entry nameEGLN3_MOUSE
AccessionPrimary (citable) accession number: Q91UZ4
Secondary accession number(s): Q3TCG8 expand/collapse secondary AC list , Q8C8M6, Q8CCA8, Q8R5C7
Entry history
Integrated into UniProtKB/Swiss-Prot: June 16, 2003
Last sequence update: December 1, 2001
Last modified: July 9, 2014
This is version 108 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot