Coiled-coil Coactivators Play a Structural Role Mediating Interactions in Hypoxia Inducible Factor Heterodimerization [Gene Regulation]

January 27th, 2015 by Guo, Y., Scheuermann, T. H., Partch, C. L., Tomchick, D. R., Gardner, K. H.

The hypoxia inducible factor complex (HIF-α/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-α 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-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, therefore participating more directly in HIF-dependent gene transcription than previously anticipated.