Prolyl hydroxylase EGLN2

Function

Prolyl hydroxylase that mediates hydroxylation of proline residues in target proteins, such as ATF4, IKBKB, CEP192 and HIF1A. Target proteins are preferentially recognized via a LXXLAP motif. 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-kappa-B activation in hypoxic conditions. Also mediates hydroxylation of ATF4, leading to decreased protein stability of ATF4 (By similarity).

Classification

Family (Pfam)

PF13640 2OG-FeII_Oxy_3

InterPro

HIF_prolyl_hydroxylases, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph, Pro_4_hyd_alph_FE2OG_OXY

Functional cluster

Tubulins & Mitochondrial Metabolic Enzymes

Experimental structures · PDB · 1

• 5V1B X-ray 2.49A

A predicted model is available from AlphaFold.

Gene Ontology · 17

• GO:0005737 cytoplasm
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0016706 2-oxoglutarate-dependent dioxygenase activity
• GO:0008198 ferrous iron binding
• GO:0160082 hypoxia-inducible factor-proline dioxygenase activity
• GO:0031418 L-ascorbic acid binding
• GO:0019826 oxygen sensor activity
• GO:0031545 peptidyl-proline 4-dioxygenase activity
• GO:0045454 cell redox homeostasis
• GO:0071456 cellular response to hypoxia
• GO:0030520 estrogen receptor signaling pathway
• GO:0018401 peptidyl-proline hydroxylation to 4-hydroxy-L-proline
• GO:0045732 positive regulation of protein catabolic process
• GO:0001558 regulation of cell growth
• GO:0043523 regulation of neuron apoptotic process
• GO:0001666 response to hypoxia

Drugs targeting this protein · 4

• ROXADUSTAT inhibitor
• DAPRODUSTAT inhibitor
• MOLIDUSTAT inhibitor
• VADADUSTAT inhibitor

Related proteins · sequence + function similarity

• Prolyl hydroxylase EGLN2 0.97
• Prolyl hydroxylase EGLN2 0.97
• Egl nine homolog 1 0.81
• Egl nine homolog 1 0.78
• Egl nine homolog 1 0.77
• 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 2 0.64
• 2-oxoglutarate and iron-dependent oxygenase domain-containing protein 2 0.64
• UPF0488 protein C8orf33 0.62
• ATP-dependent RNA helicase DDX51 0.61
• Probable trehalose-phosphate phosphatase 7 0.61
• RNA-binding protein MEX3A 0.61
• Serine/threonine-protein kinase mos 0.61

Co-cited proteins · studied together in the literature

• Egl nine homolog 1 11 shared papers
• Prolyl hydroxylase EGLN3 9 shared papers
• Prolyl hydroxylase EGLN2 1 shared papers
• Centrosomal protein of 192 kDa 1 shared papers
• Transmembrane prolyl 4-hydroxylase 1 shared papers
• E3 ubiquitin-protein ligase SIAH2 1 shared papers
• Inhibitor of nuclear factor kappa-B kinase subunit beta 1 shared papers
• Egl nine homolog 1 1 shared papers
• Prolyl hydroxylase EGLN2 1 shared papers
• Prolyl hydroxylase EGLN3 1 shared papers
• Prolyl hydroxylase EGLN3 1 shared papers
• von Hippel-Lindau tumor suppressor homolog 1 shared papers

Literature · 23 cited papers

• 1,2,4-Triazolo-[1,5-a]pyridine HIF Prolylhydroxylase Domain-1 (PHD-1) Inhibitors With a Novel Monodentate Binding Interaction. J. Med. Chem. · 2017
• PHD1 links cell-cycle progression to oxygen sensing through hydroxylation of the centrosomal protein Cep192. Dev. Cell · 2013
• Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
• The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat. Cell Biol. · 2012
• Biochemical characterization of human HIF hydroxylases using HIF protein substrates that contain all three hydroxylation sites. Biochem. J. · 2011
• Cellular oxygen sensing: Importins and exportins are mediators of intracellular localisation of prolyl-4-hydroxylases PHD1 and PHD2. Biochem. Biophys. Res. Commun. · 2009
• Role of the intracellular localization of HIF-prolyl hydroxylases. Biochim. Biophys. Acta · 2009
• The full-ORF clone resource of the German cDNA consortium. BMC Genomics · 2007
• Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc. Natl. Acad. Sci. U.S.A. · 2006
• Characterization of different isoforms of the HIF prolyl hydroxylase PHD1 generated by alternative initiation. Biochem. J. · 2006
• Cloning and characterization of the rat HIF-1 alpha prolyl-4-hydroxylase-1 gene. Protein Expr. Purif. · 2005
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• … and 11 more in the literature graph