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Investigations of the Underlying Mechanisms of HIF-1α and CITED2 Binding to TAZ1

By Wen-Ting Chu, Xiakun Chu, Jin Wang

Posted 02 Sep 2019
bioRxiv DOI: 10.1101/755074 (published DOI: 10.1073/pnas.1915333117)

The TAZ1 domain of CREB binding protein is crucial for transcriptional regulation and recognizes multiple targets. The interactions between TAZ1 and its specific targets are related to the cellular hypoxic negative feedback regulation. Previous experiments reported that one of the TAZ1 targets CITED2 is an efficient competitor of another target HIF-1α. Here by developing the structure-based models of TAZ1 complexes we have uncovered the underlying mechanisms of the competitions between HIF-1α and CITED2 binding to TAZ1. Our results are consistent with the experimental hypothesis on the competition mechanisms and the apparent affinity. In addition, the simulations prove the dominant position of forming TAZ1-CITED2 complex in both thermodynamics and kinetics. For thermodynamics, TAZ1-CITED2 is the lowest basin located on the free energy surface of binding in the ternary system. For kinetics, the results suggest that CITED2 binds to TAZ1 faster than HIF-1α. Besides, the analysis of contact map and f values in this study will be helpful for further experiments on TAZ1 systems.

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