7LVS

The CBP TAZ1 Domain in Complex with a CITED2-HIF-1-Alpha Fusion Peptide

Summary for 7LVS

• Entry DOI: 10.2210/pdb7lvs/pdb
• Descriptor: Histone lysine acetyltransferase CREBBP, Cbp/p300-interacting transactivator 2,Hypoxia-inducible factor 1-alpha, ZINC ION, ... (4 entities in total)
• Functional Keywords: complex, intrinsically disordered protein, transcription
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 2
• Total formula weight: 19000.85

Authors

Appling, F.D.,Berlow, R.B.,Stanfield, R.L.,Dyson, H.J.,Wright, P.E. (deposition date: 2021-02-26, release date: 2021-07-28, Last modification date: 2024-05-22)

Primary citation

Appling, F.D.,Berlow, R.B.,Stanfield, R.L.,Dyson, H.J.,Wright, P.E.
The molecular basis of allostery in a facilitated dissociation process.
Structure, 29:1327-1338.e5, 2021

PubMed Abstract: 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-1α 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-1α 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-1α 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-1α interaction motifs, providing molecular-level insights into the allosteric switch that terminates the hypoxic response.

PubMed: 34520739
DOI: 10.1016/j.str.2021.07.011

Experimental method

X-RAY DIFFRACTION (2.02 Å)