交易激励
Wnt信号通路
转录因子
连环素
细胞生物学
基因表达调控
生物
组蛋白
信号转导
化学
基因
遗传学
作者
Alexandra D. Brown,Connor Cranstone,Denis J. Dupré,David N. Langelaan
标识
DOI:10.1016/j.ijbiomac.2023.124155
摘要
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.
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