4pky
From Proteopedia
ARNT/HIF transcription factor/coactivator complex
Structural highlights
Disease[EPAS1_HUMAN] Defects in EPAS1 are the cause of familial erythrocytosis type 4 (ECYT4) [MIM:611783]. ECYT4 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin concentration and hematocrit, and normal platelet and leukocyte counts.[1] [2] [3] [4] Function[ARNT_HUMAN] Required for activity of the Ah (dioxin) receptor. This protein is required for the ligand-binding subunit to translocate from the cytosol to the nucleus after ligand binding. The complex then initiates transcription of genes involved in the activation of PAH procarcinogens. The heterodimer with HIF1A or EPAS1/HIF2A functions as a transcriptional regulator of the adaptive response to hypoxia. [EPAS1_HUMAN] Transcription factor involved in the induction of oxygen regulated genes. Binds to core DNA sequence 5'-[AG]CGTG-3' within the hypoxia response element (HRE) of target gene promoters. 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 seems to require recruitment of transcriptional coactivators such as CREBPB and probably EP300. Interaction with redox regulatory protein APEX seems to activate CTAD. [TACC3_MOUSE] Plays a role in the microtubule-dependent coupling of the nucleus and the centrosome. Involved in the processes that regulate centrosome-mediated interkinetic nuclear migration (INM) of neural progenitors. May be involved in the control of cell growth and differentiation. May have a role in embryonic development.[5] Publication Abstract from PubMedThe hypoxia inducible factor complex (HIF-alpha/ARNT) requires association with several transcription coactivators for a successful cellular response to hypoxic stress. In addition to the conventional global transcription coactivator CBP/p300 that binds to the HIF-alpha transactivation domain (TAD), a new group of transcription coactivators called the coiled-coil coactivators (CCCs) interact directly with the second PER-ARNT-SIM (PAS) domain of ARNT (ARNT PAS-B). These less studied transcription coactivators play essential roles in the HIF-dependent hypoxia response and CCCs misregulation is associated with several forms of cancer. To better understand CCC protein recruitment by the heterodimeric HIF transcription factor, we used X-ray crystallography, NMR spectroscopy and biochemical methods to investigate the structure of the ARNT PAS-B domain in complex with the C-terminal fragment of a coiled-coil coactivator protein: transforming acidic coiled-coil coactivator 3 (TACC3). We found that the HIF-2alpha PAS-B domain also directly interacts with TACC3, motivating an NMR data-derived model suggesting a means by which TACC3 could form a ternary complex with HIF-2alpha PAS-B and ARNT PAS-B via beta-sheet/coiled-coil interactions. These findings suggest that TACC3 could be recruited as a bridge to cooperatively mediate between the HIF-2alpha PAS-B/ARNT PAS-B complex, therefore participating more directly in HIF-dependent gene transcription than previously anticipated. Coiled-coil Coactivators Play a Structural Role Mediating Interactions in Hypoxia Inducible Factor Heterodimerization.,Guo Y, Scheuermann TH, Partch CL, Tomchick DR, Gardner KH J Biol Chem. 2015 Jan 27. pii: jbc.M114.632786. PMID:25627682[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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