1. Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function
- Author
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Benjamin Bourgeois, Tianshu Gui, Diana Hoogeboom, Henry G. Hocking, Gesa Richter, Emil Spreitzer, Martin Viertler, Klaus Richter, Tobias Madl, and Boudewijn M.T. Burgering
- Subjects
NMR spectroscopy ,structural biology ,intrinsically disordered proteins ,post-translational modification ,phosphorylation ,Wnt signaling ,Biology (General) ,QH301-705.5 - Abstract
Summary: 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.
- Published
- 2021
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