Multiple regulatory intrinsically disordered motifs control FOXO4 transcription factor binding and function

Abstract

Highlights d The interaction network between FOXO4 and b-catenin is deciphered d FOXO4 autoinhibition interferes with DNA binding and is counteracted by b-catenin d FOXO4 exists in multiple conformations regulated by phosphorylation and co-factors d ICAT switches between FOXO4 and TCF/LEF transcription factors

FOXO transcription factors differ in their dynamics and intra/intermolecular interactions

“…We identified regions in FOXO FH domains that differ in terms of their dynamics, and we determined that these differences are due to slight variations in amino acid sequence. Furthermore, we show that the intra-molecular interactions between the FH and transactivation domains (TADs) recently discovered in FOXO3 and FOXO4 ( Bourgeois et al., 2021 ; Kim et al., 2021 ; Wang et al., 2008 ) are also conserved in FOXO1 and FOXO6. Strikingly, we found that these interactions take place between FH domains and TADs of different FOXOs, provide the possibility of heterodimeric interaction with putative biological function.…”

“…The FH domains harbor a conserved N-terminal Trp-Gly motif that is especially affected in FOXO1, FOXO4 and FOXO6 upon binding to the CR3. These residues have been previously shown to be involved in intramolecular interactions in FOXO3 and FOXO4 ( Bourgeois et al., 2021 ; Wang et al., 2008 ). Interestingly, in FOXO3 binding of the CR3 to the FH domain cause only weak chemical shift perturbations in this region, indicating a weaker binding.…”

“…It has been shown for a few TFs, including p53, CCAAT/Enhancer-binding Protein β, FOXO3 and FOXO4, that their disordered regions can interact with their folded DNA-binding domains and regulate DNA binding ( Bourgeois et al., 2021 ; Kim et al., 2021 ; Wang et al., 2008 ; Tafvizi et al., 2011 ; Krois et al., 2018 ; Lee et al., 2010 ). In the case of FOXO3 and FOXO4, the disordered CR3s bind to the FH domain on a surface overlapping with the DNA binding site ( Bourgeois et al., 2021 ; Kim et al., 2021 ; Wang et al., 2008 ). This FH-CR3 binding interaction was shown to inhibit DNA binding in FOXO4 ( Bourgeois et al., 2021 ).…”

“…In the case of FOXO3 and FOXO4, the disordered CR3s bind to the FH domain on a surface overlapping with the DNA binding site ( Bourgeois et al., 2021 ; Kim et al., 2021 ; Wang et al., 2008 ). This FH-CR3 binding interaction was shown to inhibit DNA binding in FOXO4 ( Bourgeois et al., 2021 ). As both the FH domain and the CR3 are conserved in FOXO1 and FOXO6 ( Fig.…”

“…Recently, a mechanism for the regulation of FOXO transcriptional activity and specificity has been proposed, in which binding of the CR3 with the FH domain represses DNA binding. ( Bourgeois et al., 2021 ; Kim et al., 2021 ).

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