Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Bourgeois, B; Spreitzer, E; Platero-Rochart, D; Paar, M; Zhou, Q; Usluer, S; de, Keizer, PLJ; Burgering, BMT; Sánchez-Murcia, PA; Madl, T.
The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI.
Nat Commun. 2025; 16(1):5672
Doi: 10.1038/s41467-025-60844-9
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- Führende Autor*innen der Med Uni Graz
- Bourgeois Benjamin Michel Rene
- Madl Tobias
- Spreitzer Emil
- Co-Autor*innen der Med Uni Graz
- Paar Margret
- Platero Rochart Daniel de Jesus
- Sánchez Murcia Pedro Alejandro
- Usluer Sinem
- Zhou Qishun
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- Abstract:
- A central process contributing to the phenotype of aging is cellular senescence. We recently identified the FOXO4 - p53 axis as pivotal in maintaining the viability of senescent cells, and that senescent cells can be targeted selectively with the senolytic peptide FOXO4-DRI. Here, we solve the solution NMR structural models of the p53 transactivation domain in complex with the FOXO4 forkhead domain and in complex with FOXO4-DRI. Strikingly, we find that the disordered FOXO4-DRI binds to the disordered p53TAD2 and forms a transiently folded complex. In this complex, both, the FOXO4-derived region and the cationic cell permeability peptide contribute to the interaction. Furthermore, we show that p53 phosphorylation enhances the affinity for both FOXO4 and FOXO4-DRI. Summarizing we provide a detailed characterization of the interaction of p53 with FOXO4 and FOXO4-DRI which is the basis for development of p53 inhibitors to treat diseases linked to cellular senescence such as cancers.
- Find related publications in this database (using NLM MeSH Indexing)
- Tumor Suppressor Protein p53 - metabolism, chemistry, genetics
- Humans - administration & dosage
- Forkhead Transcription Factors - metabolism, chemistry, genetics
- Cell Cycle Proteins - metabolism, chemistry
- Cellular Senescence - administration & dosage
- Protein Binding - administration & dosage
- Protein Domains - administration & dosage
- Phosphorylation - administration & dosage
- Transcription Factors - metabolism, chemistry, genetics
- Transcriptional Activation - administration & dosage
- Models, Molecular - administration & dosage