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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Allosteric and Dominant-Negative Effects in a p53 Core Heterotetramer
Han Zhou1, Tao Zhou1, Shiwei Yan1,2
1School of Physics and Astronomy, Beijing Normal University, Beijing 100875, China.
Abstract:
The tumor suppressor protein p53 is one of the most frequently mutated proteins in cancer cells and is a critical target for anticancer therapies. In the nucleus, the p53 core domain binds DNA response elements as a tetramer to regulate gene transcription. During early cancer development, mutant and wild-type p53 coexist and assemble into a heterotetramer. Experimental studies confirm that the R249S mutant exerts a dominant-negative effect on wild-type p53, but the underlying molecular mechanisms, particularly how allosteric inhibition mediates the effect, remain unclear. Here, we employed all-atom molecular dynamics simulations to investigate how the R249S mutation causes dominant-negative effects in the p53 heterotetramer. Our simulations show that the mutation drives the reorganization of interfacial interactions in the heterotetramer through multiple allosteric pathways. Interestingly, the wild-type subunit forms more stable interactions with the mutant subunit than it does with wild-type subunits to adapt to the negative effects induced by the mutation in the protein.
Insights
The R249S mutation in tumor suppressor p53 (protein 53) disrupts its function by altering protein interactions. This study reveals how mutant p53 (protein 53) negatively impacts wild-type p53 (protein 53) through allosteric pathways.
Area of Science:
- Molecular Biology
- Biochemistry
- Cancer Research
Background:
- The tumor suppressor protein p53 (protein 53) is frequently mutated in cancer.
- Mutant and wild-type p53 (protein 53) coexist in early cancer development, forming heterotetramers.
- The R249S mutant p53 (protein 53) exhibits a dominant-negative effect on wild-type p53 (protein 53), but the mechanism is unclear.
Purpose of the Study:
- To investigate the molecular mechanisms by which the R249S mutation causes dominant-negative effects in the p53 (protein 53) heterotetramer.
- To elucidate the role of allosteric inhibition in mediating the dominant-negative effect.
Main Methods:
- All-atom molecular dynamics simulations were employed.
- Analysis of interfacial interactions within the p53 (protein 53) heterotetramer.
Main Results:
- The R249S mutation reorganizes interfacial interactions in the p53 (protein 53) heterotetramer via multiple allosteric pathways.
- Wild-type p53 (protein 53) subunits form more stable interactions with the R249S mutant subunit than with other wild-type subunits.
- These altered interactions are an adaptive response to the mutation's negative effects.
Conclusions:
- The R249S mutation induces dominant-negative effects by disrupting the structural integrity and function of the p53 (protein 53) heterotetramer.
- Allosteric pathways mediate the transmission of the mutation's effects throughout the protein.
- Understanding these mechanisms is crucial for developing targeted anticancer therapies.
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