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

Journal Article · · Journal of Biological Chemistry
 [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)
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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 gene transcription than previously anticipated.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-06CH11357; R01 GM081875; P01 CA095471; F32 CA130441; RP100846; RP130513
OSTI ID:
1208680
Journal Information:
Journal of Biological Chemistry, Vol. 290, Issue 12; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 19 works
Citation information provided by
Web of Science

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Cited By (8)

Structural integration in hypoxia-inducible factors journal August 2015
The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations journal May 2017
Hypoxia inducible factor (HIF) as a model for studying inhibition of protein–protein interactions journal January 2017
Druggability assessment of mammalian Per–Arnt–Sim [PAS] domains using computational approaches journal January 2019
Modulation of HIF-2α PAS-B domain contributes to physiological responses journal December 2018
FGFR-TACC gene fusions in human glioma journal November 2016
FGFR3–TACC3 cancer gene fusions cause mitotic defects by removal of endogenous TACC3 from the mitotic spindle journal August 2017
Molecular analysis of NPAS3 functional domains and variants journal December 2018

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Related Subjects

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