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bioRxiv · 10.1101/2022.08.30.505852

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

Cranstone, C.·Brown, A. D.·Dupre, D. J.·Langelaan, D. N.
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Abstract

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.

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Cranstone, C., Brown, A. D., Dupre, D. J., Langelaan, D. N.. 2022-08-30. β-catenin interacts with the TAZ1 and TAZ2 domains of CBP/p300 to activate gene transcription. https://doi.org/10.1101/2022.08.30.505852

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