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The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI

Benjamin Bourgeois1, Emil Spreitzer1, Daniel Platero-Rochart1

  • 1Division of Medicinal Chemistry, Otto-Loewi Research Center, Medical University of Graz, Graz, Austria.

Nature Communications
|July 2, 2025
PubMed

Insights

Cellular senescence, a hallmark of aging, involves the FOXO4-p53 axis. Researchers structurally characterized the interaction between p53 and FOXO4-DRI, a senolytic peptide, revealing a transiently folded complex crucial for targeting senescent cells.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Cellular senescence is a key aging process.
  • The FOXO4-p53 axis is vital for senescent cell survival.
  • Senescent cells can be targeted by the senolytic peptide FOXO4-DRI.

Purpose of the Study:

  • To elucidate the structural basis of the interaction between p53 and FOXO4.
  • To characterize the complex formed by p53 and the senolytic peptide FOXO4-DRI.
  • To provide a foundation for developing p53 inhibitors for senescence-related diseases.

Main Methods:

  • Solution Nuclear Magnetic Resonance (NMR) spectroscopy
  • Structural modeling
  • Biochemical interaction studies

Main Results:

  • Solution NMR structures of p53 transactivation domain complexed with FOXO4 forkhead domain and FOXO4-DRI were determined.
  • FOXO4-DRI, a disordered peptide, binds to disordered p53TAD2, forming a transiently folded complex.
  • Both FOXO4-derived region and cationic cell permeability peptide contribute to the FOXO4-DRI/p53 interaction.
  • p53 phosphorylation increases binding affinity for both FOXO4 and FOXO4-DRI.

Conclusions:

  • Detailed structural characterization of p53 interactions with FOXO4 and FOXO4-DRI.
  • The findings support FOXO4-DRI as a senolytic agent targeting the p53-FOXO4 axis.
  • Provides a structural basis for designing novel p53 inhibitors for cancer and aging.

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