Electrostatic Forces Control the Negative Allosteric Regulation in a Disordered Protein Switch

The transcriptional adaptor zinc-binding 1 (TAZ1) domain of the transcriptional coactivator CBP/P300 and two disordered peptides, HIF-1α and CITED2, form a delicate protein switch that regulates cellular hypoxic response. In hypoxia, HIF-1α binds TAZ1 to control the transcription of adaptive genes critical for the recovery from hypoxic stress. CITED2 acts as the negative feedback regulator to rapidly displace HIF-1α and efficiently attenuate the hypoxic response. Though CITED2 and HIF-1α have the same dissociation constant (K_d = 10 nM) in their binary complexes with TAZ1, CITED2 is much more competitive than HIF-1α upon binding the same target TAZ1 in ternary (Berlow et al. Nature 2017, 543, 447−451). Here we demonstrate that a simple coarse-grained model can recapitulate this negative allosteric effect and provide detailed physical insights into the displacement mechanism. We find that long-range electrostatic forces are essential for the efficient displacement of HIF-1α by CITED2. The strong electrostatic interactions between CITED2 and TAZ1, along with the unique binding mode, make CITED2 much more competitive than HIF-1α in binding TAZ1.