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Title: Coiled-coil coactivators play a structural role mediating interactions in hypoxia-inducible factor heterodimerization

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. Furthermore, 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 genemore » transcription than previously anticipated.« less
 [1] ;  [1] ;  [2] ;  [1] ;  [3]
  1. Univ. of Texas, Dallas, TX (United States)
  2. Univ. of Texas, Dallas, TX (United States); Univ. of California, Santa Cruz, CA (United States)
  3. Univ. of Texas, Dallas, TX (United States); City College of New York, New York, NY (United States)
Publication Date:
OSTI Identifier:
Grant/Contract Number:
AC02-06CH11357; R01 GM081875; P01 CA095471; F32 CA130441; RP100846; RP130513
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 290; Journal Issue: 12; Journal ID: ISSN 0021-9258
American Society for Biochemistry and Molecular Biology
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; crystal structure; hypoxia-inducible factor (HIF); nuclear magnetic resonance (NMR); transcription coactivator; transcription regulation; ARNT; TACC3; coiled-coil coactivator recruitment