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

The transcriptional co-regulator β-catenin is a critical member of the canonical Wnt signaling pathway, which plays an important role in regulating cell fate. Deregulation of the Wnt/β-catenin pathway is characteristic in the development of major types of cancer, where accumulation of β-catenin promotes cancer cell proliferation and renewal. β-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 β-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 β-catenin binds promiscuously to the TAZ1 and TAZ2 domains of CBP/p300. We then map the interaction site of the C-terminal β-catenin transactivation domain onto TAZ1 and TAZ2 using chemical-shift perturbation studies. Luciferase-based gene reporter assays indicate Asp750-Leu781 is critical to β-catenin gene activation, and mutagenesis revealed that acidic and hydrophobic residues within this region are necessary to maintain TAZ1 binding. These results outline a mechanism of Wnt/β-catenin gene regulation that underlies cell development and provides a framework to develop methods to block β-catenin dependent signaling. •β-Catenin is a transcription factor essential for Wnt signaling and implicated in cancer.•The C-terminal transactivation domain of β-catenin is intrinsically disordered.•β-Catenin has high affinity for both the TAZ1 and TAZ2 domains of CBP/p300.•The β-catenin C-terminal transactivation domain binds to a pocket of TAZ1 formed by the α1 and α4 helices.•Acidic and hydrophobic residues within β-catenin are key for binding to TAZ1.