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

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: 105.33   (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: 105.33   (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)

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1 – 10 of 116

CHEMBL2043327,CHEMBL2043004

EGLN2Tclin

IC50: 8.89

CHEMBL3646118,CHEMBL3931782

EGLN2Tclin

IC50: 6.32

CHEMBL2041169

EGLN2Tclin

IC50: 9.7

CHEMBL2041193

EGLN2Tclin

IC50: 9.7

CHEMBL2041181

EGLN2Tclin

IC50: 8.8

CHEMBL2041185

EGLN2Tclin

IC50: 9.7

CHEMBL2041175

EGLN2Tclin

IC50: 9.7

CHEMBL2043168

EGLN2Tclin

IC50: 9.52

CHEMBL2041177

EGLN2Tclin

IC50: 9.15

CHEMBL2041179

EGLN2Tclin

IC50: 8.43

Protein Data Bank (1)

1 – 1 of 1

PDB Structure Id	Ligand	Method	Resolution (Å)	M.W. (kDa)	Pub Year	Title

PDB Structure Id	M.W.	Resolution	Pub Year

Pathways (151)

Reactome (4)

KEGG (3)

PathwayCommons (3)

WikiPathways (141)

Cellular response to hypoxia (R-HSA-1234174)

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Items per page:

5

1 – 4 of 4

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)

Items per page:

10

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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• See Interactions on String-DB

HIF1A

Tchem

Family: TF

Novelty: 0.00031917

Score: 0.995

Data Source: Reactome,STRINGDB

EPAS1

Tchem

Novelty: 0.00460751

Score: 0.994

Data Source: Reactome,STRINGDB

HIF3A

Tbio

Novelty: 0.00260684

Score: 0.975

Data Source: Reactome,STRINGDB

EGLN3

Tclin

Novelty: 0.00819671

Score: 0.931

Data Source: STRINGDB

OS9

Tbio

Novelty: 0.01598375

Score: 0.927

Data Source: STRINGDB

EGLN1

Tclin

Novelty: 0.00280193

Score: 0.907

Data Source: STRINGDB

VHL

Tchem

Family: Enzyme

Novelty: 0.00323188

Score: 0.87

Data Source: STRINGDB

UNK

Tbio

Novelty: 0.00279871

Score: 0.831

Data Source: STRINGDB

SIAH2

Tbio

Family: Enzyme

Novelty: 0.01729844

Score: 0.823

Data Source: STRINGDB

PRKCA

Tchem

Family: Kinase

Novelty: 0.00099987

Score: 0.8

Data Source: STRINGDB

Publication Statistics

PubMed Score  105.33

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

Sequence

MDSPCQPQPLSQALPQLPGSSSEPLEPEPGRARMGVESYLPCPLLPSYHCPGVPSEASAGSGTPRATATS

1-70

TTASPLRDGFGGQDGGELRPLQSEGAAALVTKGCQRLAAQGARPEAPKRKWAEDGGDAPSPSKRPWARQE

70-140

NQEAEREGGMSCSCSSGSGEASAGLMEEALPSAPERLALDYIVPCMRYYGICVKDSFLGAALGGRVLAEV

140-210

EALKRGGRLRDGQLVSQRAIPPRSIRGDQIAWVEGHEPGCRSIGALMAHVDAVIRHCAGRLGSYVINGRT

210-280

KAMVACYPGNGLGYVRHVDNPHGDGRCITCIYYLNQNWDVKVHGGLLQIFPEGRPVVANIEPLFDRLLIF

280-350

WSDRRNPHEVKPAYATRYAITVWYFDAKERAAAKDKYQLASGQKGVQVPVSQPPTPT

350-407

MDSPCQPQPLSQALPQLPGSSSEPLEPEPGRARMGVESYLPCPLLPSYHCPGVPSEASAGSGTPRATATSTTASPLRDGFGGQDGGELRPLQSEGAAALVTKGCQRLAAQGARPEAPKRKWAEDGGDAPSPSKRPWARQENQEAEREGGMSCSCSSGSGEASAGLMEEALPSAPERLALDYIVPCMRYYGICVKDSFLGAALGGRVLAEVEALKRGGRLRDGQLVSQRAIPPRSIRGDQIAWVEGHEPGCRSIGALMAHVDAVIRHCAGRLGSYVINGRTKAMVACYPGNGLGYVRHVDNPHGDGRCITCIYYLNQNWDVKVHGGLLQIFPEGRPVVANIEPLFDRLLIFWSDRRNPHEVKPAYATRYAITVWYFDAKERAAAKDKYQLASGQKGVQVPVSQPPTPT

Find similar targets by:

Uniprot Keyword

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