CPLM-021459

Genbank Nucleotide ID

Protein Synonyms/Alias

HPH-1; Hypoxia-inducible factor prolyl hydroxylase 3; HIF-PH3; HIF-prolyl hydroxylase 3; HPH-3; Prolyl hydroxylase domain-containing protein 3; PHD3

Homo sapiens (Human)

Position	Peptide	Type	References
111	YCGSRLGKYYVKERS	ubiquitination	[1]
115	RLGKYYVKERSKAMV	ubiquitination	[1]
159	LNKNWDAKLHGGILR	ubiquitination	[2, 3, 4]
172	LRIFPEGKSFIADVE	ubiquitination	[1, 5]

[1] Systematic and quantitative assessment of the ubiquitin-modified proteome.
Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983]
[2] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
[3] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
[4] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
Chen Z, Zhou Y, Song J, Zhang Z.
Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
[5] Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.
Lee KA, Hammerle LP, Andrews PS, Stokes MP, Mustelin T, Silva JC, Black RA, Doedens JR.
J Biol Chem. 2011 Dec 2;286(48):41530-8. [PMID: 21987572]

Functional 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. 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. EGLN3 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. 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.

DOMAIN 116 214 Fe2OG dioxygenase.
REGION 62 73 Beta(2)beta(3) 'finger-like' loop (By
REGION 88 104 Required for interaction with ADRB2.
METAL 135 135 Iron (By similarity).
METAL 137 137 Iron (By similarity).
METAL 196 196 Iron (By similarity).
BINDING 205 205 2-oxoglutarate (By similarity).

Apoptosis; Complete proteome; Cytoplasm; Dioxygenase; DNA damage; Iron; Metal-binding; Nucleus; Oxidoreductase; Polymorphism; Reference proteome; Vitamin C.

UniProt (SWISSPROT/TrEMBL); GenBank; EMBL

GO:0005829; C:cytosol; TAS:Reactome.
GO:0005654; C:nucleoplasm; TAS:Reactome.
GO:0005506; F:iron ion binding; IEA:InterPro.
GO:0031418; F:L-ascorbic acid binding; IEA:UniProtKB-KW.
GO:0016702; F:oxidoreductase activity, acting on single donors with incorporation of molecular oxygen, incorporation of two atoms of oxygen; IEA:UniProtKB-KW.
GO:0031545; F:peptidyl-proline 4-dioxygenase activity; IDA:FlyBase.
GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IEP:UniProtKB.
GO:0018401; P:peptidyl-proline hydroxylation to 4-hydroxy-L-proline; IDA:FlyBase.
GO:0018126; P:protein hydroxylation; IDA:UniProtKB.
GO:0042127; P:regulation of cell proliferation; IEP:UniProtKB.
GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
GO:0061418; P:regulation of transcription from RNA polymerase II promoter in response to hypoxia; TAS:Reactome.
GO:0006974; P:response to DNA damage stimulus; IEA:UniProtKB-KW.

IPR005123; Oxoglu/Fe-dep_dioxygenase.
IPR006620; Pro_4_hyd_alph.

PF13640; 2OG-FeII_Oxy_3