Nature 543, 447–451 (2017)

Recovery from stress due to heterogeneous or fluctuating oxygen levels involves the transcription factor HIF-1α, which is stabilized during hypoxia. HIF-1α and the negative feedback regulator CITED2, one of its downstream targets, both bind to the TAZ1 domain of the transcriptional coactivators CBP and p300 via α-helices and conserved LPXL motifs that exist within intrinsically disordered regions of CITED2 and HIF-1α. These similar binding events raise the question of how CITED2 regulates HIF-1α removal from TAZ1, which is known to be critical for the CITED2 feedback mechanism during hypoxia. To study this, Berlow et al. used NMR spectroscopy to characterize what they expected to be a 1:1:1 complex between TAZ1, HIF-1α and CITED2, given the similar binding affinities of the two TAZ1 binders. However, they detected only the TAZ1–CITED2 complex, indicating that CITED2 could fully displace HIF-1α, a conclusion that was supported by fluorescence anisotropy competition experiments. Stopped-flow fluorescence experiments and NMR titrations found a transient ternary complex between HIF-1α, TAZ1 and CITED2. Upon formation of the ternary complex, CITED2 promotes a conformational change in TAZ1 that facilitates HIF-1α dissociation. These findings highlight the functional relevance of intrinsically disordered protein regions in a key feedback mechanism during hypoxia.