Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria.
Oncode Institute and Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands.
Cell Rep. 2021 Jul 27;36(4):109446. doi: 10.1016/j.celrep.2021.109446.
Transcription factors harbor defined regulatory intrinsically disordered regions (IDRs), which raises the question of how they mediate binding to structured co-regulators and modulate their activity. Here, we present a detailed molecular regulatory mechanism of Forkhead box O4 (FOXO4) by the structured transcriptional co-regulator β-catenin. We find that the disordered FOXO4 C-terminal region, which contains its transactivation domain, binds β-catenin through two defined interaction sites, and this is regulated by combined PKB/AKT- and CK1-mediated phosphorylation. Binding of β-catenin competes with the autoinhibitory interaction of the FOXO4 disordered region with its DNA-binding Forkhead domain, and thereby enhances FOXO4 transcriptional activity. Furthermore, we show that binding of the β-catenin inhibitor protein ICAT is compatible with FOXO4 binding to β-catenin, suggesting that ICAT acts as a molecular switch between anti-proliferative FOXO and pro-proliferative Wnt/TCF/LEF signaling. These data illustrate how the interplay of IDRs, post-translational modifications, and co-factor binding contribute to transcription factor function.
转录因子具有定义明确的调节性无规则区域（IDR），这就提出了一个问题，即它们如何介导与结构共调节剂的结合并调节其活性。在这里，我们通过结构转录共调节剂β-catenin 呈现了 Forkhead box O4（FOXO4）的详细分子调节机制。我们发现，包含其转录激活结构域的无序 FOXO4 C 端区域通过两个定义的相互作用位点与β-catenin 结合，这受到 PKB/AKT 和 CK1 介导的磷酸化的调节。β-catenin 的结合与 FOXO4 无序区域与其 DNA 结合 Forkhead 结构域的自动抑制相互作用相竞争，从而增强 FOXO4 的转录活性。此外，我们表明，β-catenin 抑制剂蛋白 ICAT 的结合与 FOXO4 与 β-catenin 的结合兼容，这表明 ICAT 作为抗增殖 FOXO 和促增殖 Wnt/TCF/LEF 信号之间的分子开关。这些数据说明了 IDR、翻译后修饰和共因子结合如何相互作用以促进转录因子的功能。
