Intrinsically Disordered Transactivation Domains Bind to TAZ1 Domain of CBP via Diverse Mechanisms.

CREB-binding protein is a multidomain transcriptional coactivator whose transcriptional adaptor zinc-binding 1 (TAZ1) domain mediates interactions with a number of intrinsically disordered transactivation domains (TADs), including the CREB-binding protein/p300-interacting transactivator with ED-rich tail, the hypoxia inducible factor 1α, p53, the signal transducer and activator of transcription 2, and the NF-κB p65 subunit. These five disordered TADs undergo partial disorder-to-order transitions upon binding TAZ1, forming fuzzy complexes with helical segments. Interestingly, they wrap around TAZ1 with different orientations and occupy the binding sites with various orders. To elucidate the microscopic molecular details of the binding processes of TADs with TAZ1, in this work, we carried out extensive molecular dynamics simulations using a coarse-grained topology-based model. After careful calibration of the models to reproduce the residual helical contents and binding affinities, our simulations were able to recapitulate the experimentally observed flexibility profiles. Although great differences exist in the complex structures, we found similarities between hypoxia inducible factor 1α and signal transducer and activator of transcription 2 as well as between CREB-binding protein/p300-interacting transactivator with ED-rich tail and NF-κB p65 subunit in the binding kinetics and binding thermodynamics. Although the origins of similarities and differences in the binding mechanisms remain unclear, our results provide some clues that indicate that binding of TADs to TAZ1 could be templated by the target as well as encoded by the TADs.