Residual Structure of Intrinsically Disordered Transactivation Domains Regulates Their Binding Mechanisms to the TAZ1 Domain of CBP

Abstract

The CREB binding protein (CBP) is a multifunctional transcription coactivator. The TAZ1 domain of CBP interacts with various intrinsically disordered transactivation domains (TADs), including CITED2, HIF-1α, p53, STAT2, and RelA. In our recent work, we found that the binding mechanisms of these five TADs can be divided into three groups by analyzing the conformational transition rate constants and binding free energy landscapes. Our work provides some clues suggesting that binding of TADs to TAZ1 is encoded by the TADs as well as templated by the TAZ1. The five TADs wrap around TAZ1 and form helical segments upon binding. Helical segments are important molecular recognition elements and their stability plays a role in regulating the binding process. In this work, we investigated the roles helical segments played in the binding processes of TADs with TAZ1 via molecular dynamics simulations using coarse-grained topology-based models. We first modulated the intramolecular interaction strength within TADs to increase or decrease their helicity. We then simulated the binding processes of TADs with various degree of helicity to TAZ1. Consistent with previous works on other protein complexes, increasing the TAD helicity generally increases the stability of the TAD/TAZ1 complex. However, since TAZ1 has four binding sites for TADs binding and a TAD molecule may contain multiple helical segments, the effect of individual helical segment varies significantly. Kinetic analysis also shows heterogeneous effects of helicity on the overall binding rate constant and conformational transition rate constants. Therefore, the current work further supports our previous finding that binding of TADs to TAZ1 is encoded by the TADs as well as templated by the TAZ1.