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Publication Abstract from PubMed

Facilitated dissociation provides a mechanism by which high-affinity complexes can be rapidly disassembled. The negative feedback regulator CITED2 efficiently downregulates the hypoxic response by displacing the hypoxia-inducible transcription factor HIF-1alpha from the TAZ1 domain of the transcriptional coactivators CREB-binding protein (CBP) and p300. Displacement occurs by a facilitated dissociation mechanism involving a transient ternary intermediate formed by binding of the intrinsically disordered CITED2 activation domain to the TAZ1:HIF-1alpha complex. The short lifetime of the intermediate precludes straightforward structural investigations. To obtain insights into the molecular determinants of facilitated dissociation, we model the ternary intermediate by generating a fusion peptide composed of the primary CITED2 and HIF-1alpha binding motifs. X-ray crystallographic and NMR studies of the fusion peptide complex reveal TAZ1-mediated negative cooperativity that results in nearly mutually exclusive binding of specific CITED2 and HIF-1alpha interaction motifs, providing molecular-level insights into the allosteric switch that terminates the hypoxic response.

The molecular basis of allostery in a facilitated dissociation process.,Appling FD, Berlow RB, Stanfield RL, Dyson HJ, Wright PE Structure. 2021 Dec 2;29(12):1327-1338.e5. doi: 10.1016/j.str.2021.07.011. Epub , 2021 Sep 13. PMID:34520739^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.