Tclin EGLN2 Egl nine homolog 2

Protein Summary

Description

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. The hypoxia inducible factor (HIF) is a transcriptional complex that is involved in oxygen homeostasis. At normal oxygen levels, the alpha subunit of HIF is targeted for degration by prolyl hydroxylation. This gene encodes an enzyme responsible for this post-translational modification. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream RAB4B (RAB4B, member RAS oncogene family) gene. [provided by RefSeq, Feb 2011]

Uniprot Accession IDs

• Q96KS0
• A8K5S0
• Q8WWY4
• Q9BV14

Gene Name

• EGLN2

Ensembl ID

• ENST00000303961
• ENSP00000307080
• ENSG00000269858
• ENST00000406058
• ENSP00000385253
• ENST00000593726
• ENSP00000469686

Symbol

• EIT6
• EIT6
• PHD1
• EIT-6
• HPH-1
• HPH-3
• HIFPH1
• HIF-PH1

Knowledge Table

Most Knowledge About	Knowledge Value (0 to 1 scale)
disease perturbation	0.9
molecular function	0.86
transcription factor binding site profile	0.76
transcription factor	0.73
biological process	0.69

Related Tools

Target Illumination GWAS Analytics (TIGA)

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GENEVA

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GlyGen

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ARCHS4

ARCHS4 provides access to gene-function predictions based on RNA-seq co-expression, and gene expression levels across cell and tissues.

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IDG Development Level Summary

Tdark

These are targets about which virtually nothing is known. They do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 157.08   (req: < 5)

Gene RIFs: 50   (req: <= 3)

Antibodies: 397   (req: <= 50)

Tbio

These targets do not have known drug or small molecule activities
- AND - satisfy two or more of the following criteria:

Pubmed score: 157.08   (req: >= 5)

Gene RIFs: 50   (req: > 3)

Antibodies: 397   (req: > 50)

- OR - satisfy the following criterion:

Gene Ontology Terms: 13

Tchem

Target has at least one ChEMBL compound with an activity cutoff of < 30 nM - AND - satisfies the preceding conditions

Active Ligands: 116

Tclin

Target has at least one approved drug - AND - satisfies the preceding conditions

Active Drug: 1

Approved Drugs (1)

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1 – 1 of 1

roxadustat

EGLN2Tclin

INHIBITOR IC50 : 5.24

Active Ligands (116)

Explore Active Ligands

1 – 10 of 116

CHEMBL2040895

EGLN2Tclin

IC50 : 7.42

CHEMBL2040894

EGLN2Tclin

IC50 : 7.96

CHEMBL2043170

EGLN2Tclin

IC50 : 8.09

CHEMBL2041168

EGLN2Tclin

IC50 : 8.22

CHEMBL2041179

EGLN2Tclin

IC50 : 8.43

CHEMBL2041173

EGLN2Tclin

IC50 : 8.64

CHEMBL2041172

EGLN2Tclin

IC50 : 8.68

CHEMBL2043327,CHEMBL2043004

EGLN2Tclin

IC50 : 8.89

CHEMBL2041181

EGLN2Tclin

IC50 : 8.8

CHEMBL2043172

EGLN2Tclin

IC50 : 8.92

GWAS Traits (4)

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1 – 4 of 4

GWAS Trait	EFO ID	Study Count	SNP Count	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
hematocrit	EFO_0004348	3	4	6		92.6
hemoglobin measurement	EFO_0004509	3	4	7		92.5
red blood cell density measurement	EFO_0007978	1	1	1		82.8
cigarettes per day measurement	EFO_0006525	2	1	2		81.3

• Explore on Target Illumination GWAS Analytics (TIGA)

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GWAS Trait	EFO ID	Beta Count	Odds Ratio	Evidence (Mean Rank Score)	Provenance
hematocrit	EFO_0004348	6		92.6
hemoglobin measurement	EFO_0004509	7		92.5
red blood cell density measurement	EFO_0007978	1		82.8
cigarettes per day measurement	EFO_0006525	2		81.3

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Orthologs (8)

1 – 5 of 8

Species	Name	Source ID	Gene ID	OMA	EggNOG	Inparanoid
Chimp	egl-9 family hypoxia inducible factor 2	VGNC:14743	456049
Macaque	egl-9 family hypoxia inducible factor 2		703083
Mouse	egl-9 family hypoxia-inducible factor 2	MGI:1932287	112406
Rat	egl-9 family hypoxia-inducible factor 2	RGD:631376	308457
Dog	egl-9 family hypoxia inducible factor 2		484495

Species	Name	OMA	EggNOG	Inparanoid
Chimp	egl-9 family hypoxia inducible factor 2
Macaque	egl-9 family hypoxia inducible factor 2
Mouse	egl-9 family hypoxia-inducible factor 2
Rat	egl-9 family hypoxia-inducible factor 2
Dog	egl-9 family hypoxia inducible factor 2

Protein Structure (1 Structure, 1 AlphaFold Model)

Representation

  axes   backbone   ball+stick   cartoon   rocket   rope   spacefill

Color Scheme

  target   atomindex   bfactor   chainname   electrostatic   element   hydrophobicity   resname   sstruc

Click on a row in the table to change the structure displayed.
More information can be found at RCSB PDB

AF-Q96KS0-F1-model_v1

AlphaFold Structures Developed by DeepMind and EMBL-EBI

1 – 1 of 1

PDB Structure Id	Ligand	Method	Resolution (Å)	Residues	Fraction of Total Protein	Pub Year	Title

PDB Structure Id	Fraction of Total Protein	Resolution	Pub Year

Pathways (151)

Reactome (4)

KEGG (3)

PathwayCommons (3)

WikiPathways (141)

Cellular response to hypoxia (R-HSA-1234174)

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Data Source	Name	Explore in Pharos	Explore in Source
Reactome	Cellular response to hypoxia	76 targets	R-HSA-1234174
Reactome	Cellular responses to external stimuli	487 targets	R-HSA-8953897
Reactome	Cellular responses to stress	392 targets	R-HSA-2262752
Reactome	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	67 targets	R-HSA-1234176

Name	Explore in Pharos	Explore in Source
Cellular response to hypoxia	76 targets	R-HSA-1234174
Cellular responses to external stimuli	487 targets	R-HSA-8953897
Cellular responses to stress	392 targets	R-HSA-2262752
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	67 targets	R-HSA-1234176

Gene Ontology Terms (15)

Functions (5)

Components (2)

Processes (8)

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1 – 5 of 5

GO Term	Evidence	Assigned by
ferrous iron binding	Inferred from Direct Assay (IDA)	UniProtKB
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	Inferred from Direct Assay (IDA)	UniProtKB
oxygen sensor activity	Inferred from Direct Assay (IDA)	UniProtKB
peptidyl-proline 4-dioxygenase activity	Inferred from Direct Assay (IDA)	UniProtKB
L-ascorbic acid binding	Inferred from Electronic Annotation (IEA)	UniProtKB-KW

Protein-Protein Interactions (91)

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1 – 10 of 91

• See Interactions on String-DB

HIF1A

Tchem

Family: TF

Novelty: 0.00011503

Score: 0.995

Data Source: Reactome,STRINGDB

EPAS1

Tchem

Novelty: 0.00307448

Score: 0.994

Data Source: Reactome,STRINGDB

HIF3A

Tbio

Novelty: 0.01505965

Score: 0.975

Data Source: Reactome,STRINGDB

EGLN3

Tclin

Novelty: 0.00643992

Score: 0.931

Data Source: STRINGDB

OS9

Tbio

Novelty: 0.01490339

Score: 0.927

Data Source: STRINGDB

EGLN1

Tclin

Novelty: 0.00236525

Score: 0.907

Data Source: STRINGDB

VHL

Tchem

Family: Enzyme

Novelty: 0.00285782

Score: 0.87

Data Source: STRINGDB

UNK

Tbio

Novelty: 0.01101154

Score: 0.831

Data Source: STRINGDB

SIAH2

Tbio

Family: Enzyme

Novelty: 0.01461174

Score: 0.823

Data Source: STRINGDB

PRKCA

Tchem

Family: Kinase

Novelty: 0.00057611

Score: 0.8

Data Source: STRINGDB

Publication Statistics

PubMed Score  157.08

PubMed score by year

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PubTator Score  96.07

PubTator score by year

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Amino Acid Sequence

Residue Counts

Protein Sequence

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UniProt Keyword Find Similar Targets

3D-structure
Alternative initiation
Complete proteome
Dioxygenase
Iron
Metal-binding
Nucleus
Oxidoreductase
Phosphoprotein
Reference proteome

GWAS Trait Find Similar Targets

cigarettes per day measurement
hematocrit
hemoglobin measurement
red blood cell density measurement

MGI Phenotype Find Similar Targets

cellular phenotype
homeostasis/metabolism phenotype
muscle phenotype