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Bourgeois, B; Gui, TS; Hoogeboom, D; Hocking, HG; Richter, G; Spreitzer, E; Viertler, M; Richter, K; Madl, T; Burgering, BMT.
Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function
CELL REP. 2021; 36(4): 109446 Doi: 10.1016/j.celrep.2021.109446 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Bourgeois Benjamin Michel Rene
Madl Tobias
Co-Autor*innen der Med Uni Graz
Richter Gesa Lucia
Spreitzer Emil

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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 coregulator b-catenin. We find that the disordered FOXO4 C-terminal region, which contains its transactivation domain, binds b-catenin through two defined interaction sites, and this is regulated by combined PKB/AKT- and CK1-mediated phosphorylation. Binding of b-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 b-catenin inhibitor protein ICAT is compatible with FOXO4 binding to b-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.

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