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

Yirui Guo, Thomas H. Scheuermann, Carrie L. Partch, Diana R. Tomchick, Kevin H. Gardner

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7707-7721
Number of pages15
JournalJournal of Biological Chemistry
Volume290
Issue number12
DOIs
StatePublished - Mar 20 2015

Fingerprint

Aryl Hydrocarbon Receptor Nuclear Translocator
Transcription
CREB-Binding Protein
Crystallography
Transcriptional Activation
Nuclear magnetic resonance spectroscopy
Hypoxia
Proteins
Transcription Factors
Magnetic Resonance Spectroscopy
Genes
Nuclear magnetic resonance
X-Rays
X rays

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Coiled-coil coactivators play a structural role mediating interactions in hypoxia-inducible factor heterodimerization. / Guo, Yirui; Scheuermann, Thomas H.; Partch, Carrie L.; Tomchick, Diana R.; Gardner, Kevin H.

In: Journal of Biological Chemistry, Vol. 290, No. 12, 20.03.2015, p. 7707-7721.

Research output: Contribution to journalArticle

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