ArticleThe Journal of biological chemistry2010
A novel p53 phosphorylation site within the MDM2 ubiquitination signal: II. a model in which phosphorylation at SER269 induces a mutant conformation to p53.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 28 citations in OpenAlex.
- DeepMVP: deep learning models trained on high-quality data accurately predict PTM sites and variant-induced alterations.Nature methods · 2025Article
- A Tailored Phospho-p53 Library Probes Antibody Specificity and Recognition Limitations.Chembiochem : a European journal of chemical biology · 2025Article
- Identification of a Difluorinated Alkoxy Sulfonyl Chloride as a Novel Antitumor Agent for Hepatocellular Carcinoma through Activating Fumarate Hydratase Activity.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Investigating Conformational Dynamics and Allostery in the p53 DNA-Binding Domain Using Molecular Simulations.Methods in molecular biology (Clifton, N.J.) · 2021Article
- p53 Phosphomimetics Preserve Transient Secondary Structure but Reduce Binding to Mdm2 and MdmX.Biomolecules · 2019Article
- Simulations of mutant p53 DNA binding domains reveal a novel druggable pocket.Nucleic acids research · 2019Article
- Dysregulation and restoration of homeostatic network plasticity in fragile X syndrome mice.Neuropharmacology · 2018Article
- Molecular chaperones in the acquisition of cancer cell chemoresistance with mutatedOncotarget · 2017Article
- DNA-binding protects p53 from interactions with cofactors involved in transcription-independent functions.Nucleic acids research · 2016Article
- Impact of the adenoviral E4 Orf3 protein on the activity and posttranslational modification of p53.Journal of virology · 2015Article
- Extensive post-translational modification of active and inactivated forms of endogenous p53.Molecular & cellular proteomics : MCP · 2014Article
- Mutational analysis of the multiple-antibiotic resistance regulator MarR reveals a ligand binding pocket at the interface between the dimerization and DNA binding domains.Journal of bacteriology · 2013Article
- A novel p53 phosphorylation site within the MDM2 ubiquitination signal: I. phosphorylation at SER269 in vivo is linked to inactivation of p53 function.The Journal of biological chemistry · 2010Article
Corrections and comments
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Authors and funding
7 authors at 5 institutions in 2 countries.
Funding
Abstract
The p53 DNA-binding domain harbors a conformationally flexible multiprotein binding site that regulates p53 ubiquitination. A novel phosphorylation site exists within this region at Ser(269), whose phosphomimetic mutation inactivates p53. The phosphomimetic p53 (S269D) exhibits characteristics of mutant p53: stable binding to Hsp70 in vivo, elevated ubiquitination in vivo, inactivity in DNA binding and transcription, increased thermoinstability using thermal shift assays, and λ(max) of intrinsic tryptophan fluorescence at 403 nm rather than 346 nm, characteristic of wild type p53. These data indicate that p53 conformational stability is regulated by a phosphoacceptor site within an exposed flexible surface loop and that this can be destabilized by phosphorylation. To test whether other motifs within p53 have similarly evolved, we analyzed the effect of Ser(215) mutation on p53 function because Ser(215) is another inactivating phosphorylation site in the conformationally flexible PAb240 epitope. The p53(S215D) protein is inactive like p53(S269D), whereas p53(S215A) is as active as p53(S269A). However, the double mutant p53(S215A/S269A) was transcriptionally inactive and more thermally unstable than either individual Ser-Ala loop mutant. Molecular dynamics simulations suggest that (i) solvation of phospho-Ser(215) and phospho-Ser(269) by positive charged residues or solvent water leads to local unfolding, which is accompanied by local destabilization of the N-terminal loop and global destabilization of p53, and (ii) the double alanine 215/269 mutation disrupts hydrogen bonding normally stabilized by both Ser(215) and Ser(269). These data indicate that p53 has evolved two serine phosphoacceptor residues within conformationally flexible epitopes that normally stabilize the p53 DNA-binding domain but whose phosphorylation induces a mutant conformation to wild type p53.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.