Mechanism of Competitive Binding Between HIF‐1α and CITED2 with TAZ1

Abstract

The cellular response to hypoxia is mediated by interactions between the α‐subunit of transcription factor HIF‐1 (HIF‐1α) and the TAZ1 domain of the transcriptional coactivators CBP and p300. CITED2 negatively regulates the transcriptional activity of HIF‐1. Structure studies have revealed that HIF‐1α and CITED2 bind to a partially overlapping surface of TAZ1 with similar affinity. Although the affinity of HIF‐1α and CITED2 for binding to TAZ1 is comparable, fluorescence and NMR experiments indicated that CITED2 efficiently displaced HIF‐1α from the HIF‐1α/TAZ1 complex. In this work, the binding mechanisms for HIF‐1α/TAZ1 and CITED2/TAZ1 interactions were studied by coarse‐grained molecular dynamics simulations. We found that the structure of HIF‐1α/TAZ1 complex was more dynamic than that of the CITED2/TAZ1 complex. Free energy analysis revealed that binding free energy barrier of the CITED2/TAZ1 complex was higher than that of HIF‐1α/TAZ1 complex, suggesting that the cooperativity of CITED2/TAZ1 interaction was stronger than that of HIF‐1α/TAZ1 interaction. Detailed analysis on the binding mechanism showed that CITED2 and HIF‐1α encountered different surfaces of TAZ1 to initiate the binding process. We further investigated the competitive binding between CITED2 and HIF‐1α with TAZ1 by carried out simulations using free CITED2 with HIF‐1α/TAZ1 complex, free HIF‐1α with CITED2/TAZ1 complex, and free CITED2, HIF‐1α and TAZ1. Consistent with previous NMR experiments, we observed formation of a ternary intermediate complex. Our results indicated that the dynamic interactions between HIF‐1α and TAZ1 allowed CITED2 efficiently displaced HIF‐1α from the HIF‐1α/TAZ1 complex.Support or Funding InformationThis work was supported by National Natural Science Foundation of China (Grant 21603121 to Y.H.) and Hubei University of Technology (M. G. and Y.H.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.