ArticleProceedings of the National Academy of Sciences of the United States of America2021
A phosphorylation-dependent switch in the disordered p53 transactivation domain regulates DNA binding.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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54 citing papers in PubMed, 80 citations in OpenAlex.
- A Toxoplasma gondii-derived ROP38 protein engages Ser15/Thr18-linked p53 activation and DNA damage-associated apoptotic signaling in human cancer cells.Cell communication and signaling : CCS · 2026Article
- Study of post-translational modifications of p53 in multiple myeloma.Blood cancer journal · 2026Article
- Hierarchical multi-timescale structural dynamics of the disordered N-terminal of p53.Nature communications · 2026Article
- Article
- Disordered but rhythmic-the role of intrinsic protein disorder in eukaryotic circadian timing.FEBS letters · 2026Review
- Proteasomal control of transcription factors: mechanisms, regulation and dysregulation.Cellular and molecular life sciences : CMLS · 2026Review
- Restoration of the Y220C p53 Full-Length Mutant by PK11000: a Molecular Dynamics Study of an Intrinsically Disordered Protein.ACS omega · 2026Article
- Article
- The p53 R181C mutation accumulates through impaired deacetylation by Sirt1 and facilitates tumor development.Communications biology · 2026Article
- Article
- Citrullination negatively regulates the functions of the p53 protein and opposes its ubiquitination and degradation.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Short activation domains control chromatin association of transcription factors.bioRxiv : the preprint server for biology · 2025Article
- Competition between Nucleic Acids and Intrinsically Disordered Regions within Proteins.Accounts of chemical research · 2025Article
- The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI.Nature communications · 2025Article
- The multifunctional proline-rich domain of p53 tumor suppressor.Biochimica et biophysica acta. Reviews on cancer · 2025Review
- The DNA-PKcs/JNK/p53 pathway underlies changes in cell fate decision toward death during DNA replication catastrophe.Nucleic acids research · 2025Article
- Restoration of NOX4 signalling reverses endothelial colony-forming cell angiogenic dysfunction associated with experimental and clinical diabetes.Stem cell research & therapy · 2025Article
- Versatile roles of disordered transcription factor effector domains in transcriptional regulation.The FEBS journal · 2025Review
- A tethering mechanism underlies Pin1-catalyzed prolineProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Experimental kinetic mechanism of P53 condensation-amyloid aggregation.Biophysical journal · 2025Article
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3 authors at 1 institution in 1 country.
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Abstract
The tumor-suppressor p53 is a critical regulator of the cellular response to DNA damage and is tightly regulated by posttranslational modifications. Thr55 in the AD2 interaction motif of the N-terminal transactivation domain functions as a phosphorylation-dependent regulatory switch that modulates p53 activity. Thr55 is constitutively phosphorylated, becomes dephosphorylated upon DNA damage, and is subsequently rephosphorylated to facilitate dissociation of p53 from promoters and inactivate p53-mediated transcription. Using NMR and fluorescence spectroscopy, we show that Thr55 phosphorylation inhibits DNA-binding by enhancing competitive interactions between the disordered AD2 motif and the structured DNA-binding domain (DBD). Nonphosphorylated p53 exhibits positive cooperativity in binding DNA as a tetramer. Upon phosphorylation of Thr55, cooperativity is abolished and p53 binds initially to cognate DNA sites as a dimer. As the concentration of phosphorylated p53 is further increased, a second dimer binds and causes p53 to dissociate from the DNA, resulting in a bell-shaped binding curve. This autoinhibition is driven by favorable interactions between the DNA-binding surface of the DBD and the multiple phosphorylated AD2 motifs within the tetramer. These interactions are augmented by additional phosphorylation of Ser46 and are fine-tuned by the proline-rich domain (PRD). Removal of the PRD strengthens the AD2-DBD interaction and leads to autoinhibition of DNA binding even in the absence of Thr55 phosphorylation. This study reveals the molecular mechanism by which the phosphorylation status of Thr55 modulates DNA binding and controls both activation and termination of p53-mediated transcriptional programs at different stages of the cellular DNA damage response.
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