FOXO4 interacts with p53 TAD and CRD and inhibits its binding to DNA

0556576 - FGÚ 2023 RIV US eng J - Journal Article
Mandal, R. - Kohoutová, Klára - Petrvalská, Olivia - Horváth, M. - Srb, Pavel - Veverka, Václav - Obšilová, Veronika - Obšil, Tomáš
FOXO4 interacts with p53 TAD and CRD and inhibits its binding to DNA.
Protein Science. Roč. 31, č. 5 (2022), č. článku e4287. ISSN 0961-8368. E-ISSN 1469-896X
R&D Projects: GA ČR(CZ) GA21-02080S
Research Infrastructure: CIISB II - 90127
Institutional support: RVO:67985823 ; RVO:61388963
Keywords : DNA binding * forkhead box O 4 * nuclear magnetic resonance * protein-protein interaction * senescence * transcription factor p53
OECD category: Biochemistry and molecular biology
Impact factor: 8, year: 2022
Method of publishing: Limited access
https://doi.org/10.1002/pro.4287

Transcription factor p53 protects cells against tumorigenesis when subjected to various cellular stresses. Under these conditions, p53 interacts with transcription factor Forkhead box O (FOXO) 4, thereby inducing cellular senescence by upregulating the transcription of senescence-associated protein p21. However, the structural details of this interaction remain unclear. Here, we characterize the interaction between p53 and FOXO4 by NMR, chemical cross-linking, and analytical ultracentrifugation. Our results reveal that the interaction between p53 TAD and the FOXO4 Forkhead domain is essential for the overall stability of the p53:FOXO4 complex. Furthermore, contacts involving the N-terminal segment of FOXO4, the C-terminal negative regulatory domain of p53 and the DNA-binding domains of both proteins stabilize the complex, whose formation blocks p53 binding to DNA but without affecting the DNA-binding properties of FOXO4. Therefore, our structural findings may help to understand the intertwined functions of p53 and FOXO4 in cellular homeostasis, longevity, and stress response.
Permanent Link: http://hdl.handle.net/11104/0330737