title: Coiled-coil coactivators play a structural role mediating interactions in hypoxia-inducible factor heterodimerization.
abstract: The hypoxia-inducible factor complex (HIF-α·aryl hydrocarbon receptor nuclear translocator (ARNT)) requires association with several transcription coactivators for a successful cellular response to hypoxic stress. In addition to the conventional global transcription coactivator CREB-binding protein/p300 (CBP/p300) that binds to the HIF-α transactivation domain, 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 CCC 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-2α 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-2α PAS-B and ARNT PAS-B via β-sheet/coiled-coil interactions. These findings suggest that TACC3 could be recruited as a bridge to cooperatively mediate between the HIF-2α PAS-B·ARNT PAS-B complex, thereby participating more directly in HIF-dependent gene transcription than previously anticipated.
authors: From the Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8816 and.
authors: Yirui
authors: Y
authors: Guo
authors: From the Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8816 and.
authors: Thomas H
authors: TH
authors: Scheuermann
authors: From the Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8816 and.
authors: Carrie L
authors: CL
authors: Partch
authors: From the Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8816 and.
authors: Diana R
authors: DR
authors: Tomchick
authors: From the Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8816 and the Structural Biology Initiative, CUNY Advanced Science Research Center, and Department of Chemistry, City College of New York, New York, New York 10031 Kevin.Gardner@asrc.cuny.edu.
authors: Kevin H
authors: KH
authors: Gardner
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000737:chemistry / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D015534:Trans-Activators / Q000502:physiology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D008869:Microtubule-Associated Proteins; D015534:Trans-Activators; D000099162:Endothelial PAS Domain-Containing Protein 1; C497396:ARNT protein, human; C120551:TACC3 protein, human
keywords: ARNT; Coiled-coil Coactivator Recruitment; Crystal Structure; Hypoxia-inducible Factor (HIF); Nuclear Magnetic Resonance (NMR); TACC3; Transcription Coactivator; Transcription Regulation
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