Abstract
Intrinsically disordered proteins play important functions in various biological processes. A number of intrinsically disordered transactivation domains (TADs) interact with the TAZ1 domain of the transcriptional coactivator CREB binding protein. In this work, we focus on five disordered TADs whose structures in complex with the TAZ1 domain have been determined via solution NMR. They are CITED2, HIF-1α, p53, STAT2, and RelA. Upon binding to TAZ1, these five TADs wrap around TAZ1 and undergo partial disorder-to-order transitions. A comparison of the TAD/TAZ1 complexes shows that the five TADs wrap around TAZ1 with different orientations and occupy the four TAZ1 binding sites with various orders. To elucidate the microscopic molecular details of the heterogeneous binding processes of TADs with TAZ1, we carried out molecular dynamics simulations using a coarse-grained topology-based model. Free energy analysis showed that intramolecular native contacts increased gradually with intermolecular native contacts for the five TADs. Φ-value analysis showed that only a small fraction of native contacts were formed in the transition state. Kinetics analysis revealed distinct features for the five TADs. HIF-1α and STAT2 bind to TAZ1 with low binding rates, slow transition kinetics, and low evolving probability. CITED2 and RelA bind to TAZ1 with high binding rates, medium transition kinetics, and high evolving probability. p53 binds to TAZ1 with high binding rates, high transition kinetics, and low evolving probability. As the five TADs have low sequence similarity and bind to TAZ1 with different binding poses, the similar and different binding features should reflect the roles that TADs and TAZ1 played in the binding process. Analysis of the binding mechanisms suggests that binding of TADs to TAZ1 is encoded by the TADs as well as templated by the TAZ1.
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