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Gene & Protein in Disease Hotspots in the FOXO4: p53 interaction

exhibits a slight improvement in activity when compared Sadremomtaz, Angel Ruiz-Moreno, Alessandra
to FOXO4-DRI. It is possible that the longer FOXO4- Monti, Zayana Al-Dahmani, Benjamin B. Gyau
DRI peptide, while capable of more interactions with the Writing – original draft: Ran Zhang
p53 surface, may be impacted by the need for increased Writing – review & editing: All authors
peptide flexibility during binding to p53. In addition, the
substitution of D-amino acids may allow the peptide chain Ethics approval and consent to participate
to adopt different folding structures distinct from those Not applicable.
formed by L-amino acid peptides, further promoting their
binding to the active pocket. Consent for publication

The binding affinities suggest that the configuration, Not applicable.
order difference, and flexibility of the peptide can
significantly affect peptide affinity. This finding further Availability of data
supports the potential of truncated peptide design, Raw data are available on request from the corresponding
based on conserved hot spots, in combination with DRI author.
approaches as a promising strategy for addressing other
PPI surfaces. Moreover, our predicted model, together References
with the activity assays, strongly indicates that Pocket 1 1. Muñoz-Espín D, Cañamero M, Maraver A, et al., 2013,
and Pocket 2 are the hot spot regions of the FOXO4:p53 Programmed cell senescence during mammalian embryonic
interface. This insight provides a potential mechanism to development. Cell, 155(5): 1104–1118.
support the design of further modulators targeting the
FOXO4-DRI: p53 interaction. https://doi.org/10.1016/j.cell.2013.10.019
2. Coppé JP, Desprez PY, Krtolica A, et al., 2010, The
5. Conclusion senescence-associated secretory phenotype: The dark side of
Compared to the L peptide, the DRI exhibits a significantly tumor suppression. Annu Rev Pathol, 5: 99–118.
higher in vitro binding affinity to p53-DBD, strongly https://doi.org/10.1146/annurev-pathol-121808-102144
suggesting distinct binding modes between the two species 3. Young AR, Narita M, 2009, SASP reflects senescence. EMBO
and p53-DBD. Computational calculations support this Rep, 10(3): 228–230.
observation. A truncated form of DRI contains the crucial
region for specifically targeting the hot spot regions, as https://doi.org/10.1038/embor.2009.22
the shorter peptide retains almost full binding affinity to 4. Birch J, Gil J, 2020, Senescence and the SASP: Many
p53-DBD. While retaining binding affinity, the potential therapeutic avenues. Genes Dev, 34(23–24): 1565–1576.
to significantly reduce the size of FOXO4-DRI provides a https://doi.org/10.1101/gad.343129.120
basis for designing small molecule mimics of DRI, which 5. Campisi J, 2000, Cancer, aging and cellular senescence. In
may lead to improvements in drug-like behavior.
Vivo, 14(1): 183–188.
Acknowledgments 6. Marei HE, Althani A, Afifi N, et al., 2021, p53 signaling in
cancer progression and therapy. Cancer Cell Int, 21(1): 703.
None.
https://doi.org/10.1186/s12935-021-02396-8
Funding 7. Joerger AC, Fersht AR, 2010, The tumor suppressor p53:

The authors acknowledge financial support from the From structures to drug discovery. Cold Spring Harb Perspect
Chinese Scholarship Council (RZ and KG). Biol, 2(6): a000919.
https://doi.org/10.1101/cshperspect.a000919
Conflict of interest
8. Aubrey BJ, Kelly GL, Janic A, et al., 2018, How does p53
The authors declare that they have no competing interests. induce apoptosis and how does this relate to p53-mediated
tumour suppression? Cell Death Differ, 25: 104–113.
Author contributions
https://doi.org/10.1038/cdd.2017.169
Conceptualization: All authors 9. Fischer M, 2017, Census and evaluation of p53 target genes.
Investigation: Ran Zhang, Kai Gao, Afsaneh Sadremomtaz, Oncogene, 36(28): 3943–3956.
Angel Ruiz-Moreno, Alessandra Monti, Zayana
Al-Dahmani, Benjamin B. Gyau https://doi.org/10.1038/onc.2016.502
Formal analysis: Ran Zhang, Kai Gao, Afsaneh 10. Harris CC, 1996, p53 tumor suppressor gene: At the

Volume 2 Issue 3 (2023) 7 https://doi.org/10.36922/gpd.1491