Endothelial PAS domain-containing protein 1

Function

Transcription factor involved in the induction of oxygen regulated genes. Heterodimerizes with ARNT; heterodimer binds to core DNA sequence 5'-TACGTG-3' within the hypoxia response element (HRE) of target gene promoters (By similarity). Regulates the vascular endothelial growth factor (VEGF) expression and seems to be implicated in the development of blood vessels and the tubular system of lung. May also play a role in the formation of the endothelium that gives rise to the blood brain barrier. Potent activator of the Tie-2 tyrosine kinase expression. Activation requires recruitment of transcriptional coactivators such as CREBBP and probably EP300. Interaction with redox regulatory protein APEX1 seems to activate CTAD (By similarity).

Classification

Family (Pfam)

PF23171 bHLH_HIF1A, PF11413 HIF-1, PF08778 HIF-1a_CTAD, PF00989 PAS, PF14598 PAS_11

InterPro

bHLH_dom, HIF-1_CTAD, HIF_alpha-like, HLH_DNA-bd_sf, Nuc_translocat, PAC, PAS, PAS-like_dom_sf, PAS_fold

Functional cluster

Homeobox & Zinc-Finger Transcription Factors

Experimental structures · PDB · 42

• 1P97 NMR
• 2A24 NMR
• 3F1N X-ray 1.48A
• 3F1O X-ray 1.60A
• 3F1P X-ray 1.17A
• 3H7W X-ray 1.65A
• 3H82 X-ray 1.50A
• 4GHI X-ray 1.50A
• 4GS9 X-ray 1.72A
• 4PKY X-ray 3.20A
• 4XT2 X-ray 1.70A
• 5KIZ NMR
• … and 30 more

A predicted model is available from AlphaFold.

Gene Ontology · 27

• GO:0000785 chromatin
• GO:0005829 cytosol
• GO:0016607 nuclear speck
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0005667 transcription regulator complex
• GO:0001228 DNA-binding transcription activator activity, RNA polymerase II-specific
• GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific
• GO:0046982 protein heterodimerization activity
• GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
• GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding
• GO:0061629 RNA polymerase II-specific DNA-binding transcription factor binding
• GO:0001223 transcription coactivator binding
• GO:0001525 angiogenesis
• GO:0001974 blood vessel remodeling
• GO:0071456 cellular response to hypoxia
• GO:0030218 erythrocyte differentiation
• GO:0032364 intracellular oxygen homeostasis
• GO:0030324 lung development
• GO:0042789 mRNA transcription by RNA polymerase II
• GO:0048625 myoblast fate commitment
• GO:0120162 positive regulation of cold-induced thermogenesis
• GO:0045944 positive regulation of transcription by RNA polymerase II
• GO:2000434 regulation of protein neddylation
• GO:0006357 regulation of transcription by RNA polymerase II
• GO:0001666 response to hypoxia
• GO:0007165 signal transduction

Disease associations

• erythrocytosis, familial, 4 MONDO:0012729

Drugs targeting this protein · 1

• BELZUTIFAN inhibitor

Related proteins · sequence + function similarity

• Endothelial PAS domain-containing protein 1 0.99
• Endothelial PAS domain-containing protein 1 0.98
• Hypoxia-inducible factor 1-alpha 0.89
• Aryl hydrocarbon receptor 0.85
• Aryl hydrocarbon receptor 0.85
• Aryl hydrocarbon receptor 0.85
• Aryl hydrocarbon receptor 0.85
• Aryl hydrocarbon receptor 0.85
• Aryl hydrocarbon receptor 0.85
• Aryl hydrocarbon receptor 0.84
• Hypoxia-inducible factor 1-alpha 0.84
• Hypoxia-inducible factor 1-alpha 0.84

Co-cited proteins · studied together in the literature

• Endothelial PAS domain-containing protein 1 1 shared papers
• Protein UL95 homolog 1 shared papers
• Aryl hydrocarbon receptor nuclear translocator 1 shared papers
• Hypoxia-inducible factor 1-alpha 2 shared papers
• Neuronal PAS domain-containing protein 1 1 shared papers
• von Hippel-Lindau disease tumor suppressor 1 shared papers
• Egl nine homolog 1 1 shared papers
• Neuronal PAS domain-containing protein 2 1 shared papers
• Basic helix-loop-helix ARNT-like protein 1 1 shared papers

Literature · 14 cited papers

• Human genetic history on the Tibetan Plateau in the past 5100 years. Sci. Adv. · 2023
• A pleiotropic hypoxia-sensitive EPAS1 enhancer is disrupted by adaptive alleles in Tibetans. Sci. Adv. · 2022
• The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans. Proc. Natl. Acad. Sci. U.S.A. · 2021
• The Kaposi's Sarcoma-Associated Herpesvirus ORF34 Protein Interacts and Stabilizes HIF-2alpha via Binding to the HIF-2alpha bHLH and PAS Domains. J. Virol. · 2019
• Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature · 2014
• Two new mutations in the HIF2A gene associated with erythrocytosis. Am. J. Hematol. · 2012
• Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline. J. Biol. Chem. · 2009
• Novel exon 12 mutations in the HIF2A gene associated with erythrocytosis. Blood · 2008
• A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N. Engl. J. Med. · 2008
• Structural basis of ARNT PAS-B dimerization: use of a common beta-sheet interface for hetero- and homodimerization. J. Mol. Biol. · 2005
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Molecular mechanisms of transcription activation by HLF and HIF1alpha in response to hypoxia: their stabilization and redox signal-induced interaction with CBP/p300. EMBO J. · 1999
• … and 2 more in the literature graph