β-catenin interacts with the TAZ1 and TAZ2 domains of CBP/p300 to activate gene transcription

The transcriptional co-regulator {beta}-catenin is a critical effector of the canonical Wnt-signalling pathway, which plays a crucial role in regulating cell fate and maintaining tissue homeostasis. Deregulation of the Wnt/{beta}-catenin pathway is characteristic in the development of major types of cancer, where accumulation of {beta}-catenin promotes cancer cell proliferation and renewal. {beta}-catenin gene expression is facilitated through recruitment of co-activators such as histone acetyltransferases CBP/p300; however, the mechanism of their interaction is not fully understood. Here we investigate the interaction between the C-terminal transactivation domain of {beta}-catenin and CBP/p300. Using a combination of pulldown assays, isothermal titration calorimetry, and nuclear resonance spectroscopy we determine the disordered C-terminal region of {beta}-catenin binds promiscuously to the TAZ1 and TAZ2 domains of CBP/p300. We then map the interaction site of the C-terminal {beta}-catenin transactivation domain onto TAZ1 and TAZ2 using chemical-shift perturbation studies. Luciferase-based gene reporter assays indicate Asp750-Leu781 is critical to {beta}-catenin gene activation, and mutagenesis revealed that acidic and hydrophobic residues within this region are necessary to maintain TAZ1 binding. These results provide a mechanistic understanding of Wnt/{beta}-catenin gene regulation that underlies cell development and provide a framework to develop methods to block {beta}-catenin dependent signalling in the future.