Competitive Binding of HIF-1α and CITED2 to the TAZ1 Domain of CBP from Molecular Simulations

22 January 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Many intrinsically disordered proteins (IDPs) are involved in complex signalling networks inside the cell.
Their particular binding modes elicit different types of responses and subtle regulation of biological responses.
Here we study the binding of two disordered transactivation domains from proteins HIF-1α and CITED2, whose binding to the TAZ1 domain of CBP is critical for the hypoxic response. Experiments have shown that both IDPs compete for their shared partner, and that this competition is mediated by the formation of a ternary intermediate state. Here we use molecular simulations with a coarse-grained model to provide a glimpse of the structure of this intermediate.
We find that the conserved LP(Q/E)L motif may have a critical role in the displacement of HIF-1α by CITED2 and show a possible mechanism for the transition from the intermediate to the bound state. We also explore the role of TAZ1 dynamics in the binding. The results of our simulations are consistent with many of the experimental observations and provide a detailed molecular description of the emergent properties in the complex binding of these IDPs.


Intrinsically Disordered Proteins
Protein-protein interactions
Protein-protein binding
Coarse-grained models
Molecular dynamics


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