Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1α

Adaptation to hypoxia is mediated by transactivation of hypoxia-responsive genes by hypoxia-inducible factor-1 (HIF-1) in complex with the CBP and p300 transcriptional coactivators. We report the solution structure of the cysteine/histidine-rich 1 (CH1) domain of p300 bound to the C-terminal transactivation domain of HIF-1alpha. CH1 has a triangular geometry composed of four a-helices with three intervening Zn2+-coordinating centers. CH1 serves as a scaffold for folding of the HIF-1alpha C-terminal transactivation domain, which forms a vise-like clamp on the CH1 domain that is stabilized by extensive hydrophobic and polar interactions. The structure reveals the mechanism of specific recognition of p300 by HIF-1alpha, and shows how HIF-1alpha transactivation is regulated by asparagine hydroxylation.