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Protein

Egl nine homolog 2

Gene

EGLN2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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. 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. EGLN2 is involved in regulating hypoxia tolerance and apoptosis in cardiac and skeletal muscle. Also regulates susceptibility to normoxic oxidative neuronal death. Links oxygen sensing to cell cycle and primary cilia formation by hydroxylating the critical centrosome component CEP192 which promotes its ubiquitination and subsequent proteasomal degradation. Hydroxylates IKBKB, mediating NF-kappaB activation in hypoxic conditions. Target proteins are preferentially recognized via a LXXLAP motif.6 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)DescriptionActionsGraphical viewLength
Metal bindingi297IronPROSITE-ProRule annotation1
Metal bindingi299IronPROSITE-ProRule annotation1
Metal bindingi358IronPROSITE-ProRule annotation1
Binding sitei3672-oxoglutaratePROSITE-ProRule annotation1

GO - Molecular functioni

GO - Biological processi

  • cell redox homeostasis Source: UniProtKB
  • intracellular estrogen receptor signaling pathway Source: UniProtKB
  • peptidyl-proline hydroxylation to 4-hydroxy-L-proline Source: FlyBase
  • positive regulation of protein catabolic process Source: UniProtKB
  • regulation of cell growth Source: UniProtKB
  • regulation of neuron apoptotic process Source: UniProtKB
  • regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: Reactome
  • response to hypoxia Source: UniProtKB

Keywordsi

Molecular functionDioxygenase, Oxidoreductase
LigandIron, Metal-binding, Vitamin C

Enzyme and pathway databases

BioCyciMetaCyc:ENSG00000171570-MONOMER
BRENDAi1.14.11.2 2681
1.14.11.29 2681
ReactomeiR-HSA-1234176 Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
SIGNORiQ96KS0

Names & Taxonomyi

Protein namesi
Recommended name:
Egl nine homolog 2 (EC:1.14.11.29)
Alternative name(s):
Estrogen-induced tag 6
HPH-3
Hypoxia-inducible factor prolyl hydroxylase 1
Short name:
HIF-PH1
Short name:
HIF-prolyl hydroxylase 1
Short name:
HPH-1
Prolyl hydroxylase domain-containing protein 1
Short name:
PHD1
Gene namesi
Name:EGLN2
Synonyms:EIT6
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 19

Organism-specific databases

EuPathDBiHostDB:ENSG00000269858.5
HGNCiHGNC:14660 EGLN2
MIMi606424 gene
neXtProtiNX_Q96KS0

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi1M → A: Leads to expression of isoform p40 only. 1 Publication1
Mutagenesisi34M → A: Leads to expression of isoform p43 only. 1 Publication1
Mutagenesisi102K → A: Retained in the nucleus. 1 Publication1
Mutagenesisi106R → A: Retained in the nucleus. 1 Publication1
Mutagenesisi113R → A: Retained in the nucleus. 1 Publication1
Mutagenesisi119R → A: Cytoplasmic and nuclear localization. Reduced transcriptional activity of HIF1A as for wild type. 1 Publication1
Mutagenesisi134R → A: Retained in the nucleus. 1 Publication1
Mutagenesisi297H → A: Eliminates hydroxylase activity. 1 Publication1
Mutagenesisi299D → A: Eliminates hydroxylase activity. 1 Publication1
Mutagenesisi358H → A: Eliminates hydroxylase activity. 2 Publications1
Mutagenesisi367R → A: Eliminates hydroxylase activity. 1 Publication1
Mutagenesisi367R → K: Eliminates hydroxylase activity on a HIF1A peptide. 1 Publication1

Organism-specific databases

DisGeNETi112398
OpenTargetsiENSG00000269858
PharmGKBiPA27671

Chemistry databases

ChEMBLiCHEMBL3028
DrugBankiDB04847 FG-4592
DB00126 Vitamin C
GuidetoPHARMACOLOGYi2832

Polymorphism and mutation databases

BioMutaiEGLN2
DMDMi32129513

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002066641 – 407Egl nine homolog 2Add BLAST407

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei130PhosphoserineCombined sources1

Keywords - PTMi

Phosphoprotein

Proteomic databases

MaxQBiQ96KS0
PaxDbiQ96KS0
PeptideAtlasiQ96KS0
PRIDEiQ96KS0

PTM databases

iPTMnetiQ96KS0
PhosphoSitePlusiQ96KS0

Expressioni

Tissue specificityi

Expressed in adult and fetal heart, brain, liver, lung, skeletal muscle, and kidney. Also expressed in testis and placenta. Highest levels in adult brain, placenta, lung, kidney, and testis. Expressed in hormone responsive tissues, including normal and cancerous mammary, ovarian and prostate epithelium.1 Publication

Inductioni

By estrogen. Isoform p43 is induced by hypoxia leading to protein stability. Isoform p40 repressed by hypoxia. Both isoforms are induced by proteasomal inhibitor MG132 (at protein level).4 Publications

Gene expression databases

BgeeiENSG00000269858
CleanExiHS_EGLN2
ExpressionAtlasiQ96KS0 baseline and differential
GenevisibleiQ96KS0 HS

Organism-specific databases

HPAiHPA056649

Interactioni

Subunit structurei

Interacts (preferably isoform p40) with SIAH2; the interaction targets both SIAH2 isoforms for proteasomal degradation in vitro. Interacts with LIMD1, WTIP and AJUBA.2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
HIF1AQ166652EBI-726614,EBI-447269

Protein-protein interaction databases

BioGridi125184, 24 interactors
IntActiQ96KS0, 6 interactors
MINTiQ96KS0
STRINGi9606.ENSP00000307080

Chemistry databases

BindingDBiQ96KS0

Structurei

Secondary structure

1407
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi173 – 180Combined sources8
Helixi182 – 188Combined sources7
Beta strandi190 – 195Combined sources6
Helixi199 – 215Combined sources17
Beta strandi239 – 243Combined sources5
Helixi251 – 265Combined sources15
Turni266 – 269Combined sources4
Beta strandi270 – 273Combined sources4
Beta strandi282 – 287Combined sources6
Beta strandi294 – 297Combined sources4
Beta strandi305 – 313Combined sources9
Helixi320 – 323Combined sources4
Beta strandi327 – 329Combined sources3
Beta strandi332 – 335Combined sources4
Beta strandi338 – 340Combined sources3
Beta strandi346 – 351Combined sources6
Beta strandi358 – 360Combined sources3
Beta strandi363 – 365Combined sources3
Beta strandi367 – 375Combined sources9
Helixi377 – 385Combined sources9
Helixi392 – 395Combined sources4

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
5V1BX-ray2.49A167-403[»]
ProteinModelPortaliQ96KS0
SMRiQ96KS0
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini278 – 376Fe2OG dioxygenasePROSITE-ProRule annotationAdd BLAST99

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni225 – 235Beta(2)beta(3) 'finger-like' loopAdd BLAST11

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi89 – 134Bipartite nuclear localization signalAdd BLAST46

Domaini

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

Phylogenomic databases

eggNOGiKOG3710 Eukaryota
ENOG410ZHZN LUCA
GeneTreeiENSGT00390000001936
HOGENOMiHOG000013099
HOVERGENiHBG051456
InParanoidiQ96KS0
KOiK09592
OMAiGMSCGCS
OrthoDBiEOG091G03SP
PhylomeDBiQ96KS0
TreeFamiTF314595

Family and domain databases

InterProiView protein in InterPro
IPR005123 Oxoglu/Fe-dep_dioxygenase
IPR006620 Pro_4_hyd_alph
PfamiView protein in Pfam
PF13640 2OG-FeII_Oxy_3, 1 hit
SMARTiView protein in SMART
SM00702 P4Hc, 1 hit
PROSITEiView protein in PROSITE
PS51471 FE2OG_OXY, 1 hit

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative initiation. AlignAdd to basket

Isoform p43 (identifier: Q96KS0-1) [UniParc]FASTAAdd to basket
Also known as: PHD1p43

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MDSPCQPQPL SQALPQLPGS SSEPLEPEPG RARMGVESYL PCPLLPSYHC
60 70 80 90 100
PGVPSEASAG SGTPRATATS TTASPLRDGF GGQDGGELRP LQSEGAAALV
110 120 130 140 150
TKGCQRLAAQ GARPEAPKRK WAEDGGDAPS PSKRPWARQE NQEAEREGGM
160 170 180 190 200
SCSCSSGSGE ASAGLMEEAL PSAPERLALD YIVPCMRYYG ICVKDSFLGA
210 220 230 240 250
ALGGRVLAEV EALKRGGRLR DGQLVSQRAI PPRSIRGDQI AWVEGHEPGC
260 270 280 290 300
RSIGALMAHV DAVIRHCAGR LGSYVINGRT KAMVACYPGN GLGYVRHVDN
310 320 330 340 350
PHGDGRCITC IYYLNQNWDV KVHGGLLQIF PEGRPVVANI EPLFDRLLIF
360 370 380 390 400
WSDRRNPHEV KPAYATRYAI TVWYFDAKER AAAKDKYQLA SGQKGVQVPV

SQPPTPT
Length:407
Mass (Da):43,650
Last modified:December 1, 2001 - v1
Checksum:iF172E9B0482C9CF3
GO
Isoform p40 (identifier: Q96KS0-2) [UniParc]FASTAAdd to basket
Also known as: PHD1p40

The sequence of this isoform differs from the canonical sequence as follows:
     1-33: Missing.

Show »
Length:374
Mass (Da):40,168
Checksum:i228015782B7DE743
GO

Sequence cautioni

The sequence AAH01723 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti176R → P in AAK82943 (PubMed:11850811).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0388361 – 33Missing in isoform p40. CuratedAdd BLAST33

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ310544 mRNA Translation: CAC42510.1
AY040565 mRNA Translation: AAK82943.1
AK291385 mRNA Translation: BAF84074.1
AL832506 mRNA No translation available.
AC008537 Genomic DNA No translation available.
CH471126 Genomic DNA Translation: EAW57008.1
BC001723 mRNA Translation: AAH01723.1 Different initiation.
BC036051 mRNA Translation: AAH36051.1
CCDSiCCDS12567.1 [Q96KS0-1]
RefSeqiNP_444274.1, NM_053046.3 [Q96KS0-1]
NP_542770.2, NM_080732.3 [Q96KS0-1]
UniGeneiHs.515417
Hs.631539
Hs.730737

Genome annotation databases

EnsembliENST00000303961; ENSP00000307080; ENSG00000269858 [Q96KS0-1]
ENST00000406058; ENSP00000385253; ENSG00000269858 [Q96KS0-1]
ENST00000593726; ENSP00000469686; ENSG00000269858 [Q96KS0-1]
GeneIDi112398
KEGGihsa:112398
UCSCiuc002opg.5 human [Q96KS0-1]

Keywords - Coding sequence diversityi

Alternative initiation

Similar proteinsi

Entry informationi

Entry nameiEGLN2_HUMAN
AccessioniPrimary (citable) accession number: Q96KS0
Secondary accession number(s): A8K5S0, Q8WWY4, Q9BV14
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 16, 2003
Last sequence update: December 1, 2001
Last modified: May 23, 2018
This is version 155 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

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