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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
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p53 dynamics upon response element recognition explored by molecular simulations
Tsuyoshi Terakawa1, Shoji Takada1
1Department of Biophysics, Graduate School of Science, Kyoto University, Sakyo, Kyoto, Japan.
Scientific Reports
|November 25, 2015
Summary
The tumor suppressor p53 protein (p53) adopts distinct structures when searching for and binding to DNA, revealing new insights into gene regulation. This study elucidates the molecular mechanisms of p53-DNA interactions.
Area of Science:
- Molecular Biology
- Structural Biology
- Biophysics
Background:
- The p53 protein is a crucial transcription factor regulating numerous target genes.
- Understanding how p53 recognizes diverse DNA targets with structural variety is essential for comprehending stimulus-dependent gene activation.
- The molecular mechanisms underlying p53's target recognition remain largely unknown.
Purpose of the Study:
- To investigate the structure and dynamics of the full-length p53 tetramer during DNA response element (RE) recognition.
- To elucidate the molecular mechanisms by which p53 searches for and binds to its DNA targets.
- To explore the impact of response element variation on the p53-RE complex structure.
Main Methods:
- Utilized long-timescale (over 100 ms) coarse-grained molecular dynamics simulations.
- Obtained and analyzed structural ensembles of the full-length p53 tetramer bound to its response element.
- Investigated the dynamics of p53 during the search process and the effects of post-translational modifications.
Main Results:
- Revealed distinct structures of the p53 tetramer when bound to DNA compared to its searching state.
- Provided high-resolution details on intrinsically disordered regions, core domain contacts, DNA bending, and linker connectivity.
- Demonstrated how variations in the response element influence the p53-RE complex structure.
- Uncovered insights into the p53 search mechanism and the role of post-translational modifications.
Conclusions:
- The study provides unprecedented structural and dynamic details of full-length p53-DNA recognition.
- The findings offer a deeper understanding of the molecular basis for p53's sequence-specific DNA binding and gene regulation.
- This work lays the foundation for future research into p53 function and potential therapeutic strategies.
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