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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Tumorigenic p53 mutants undergo common structural disruptions including conversion to α-sheet structure
Dennis Bromley1, Valerie Daggett1,2
1Division of Biomedical and Health Informatics, Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, Washington, USA.
Abstract:
The p53 protein is a commonly studied cancer target because of its role in tumor suppression. Unfortunately, it is susceptible to mutation-associated loss of function; approximately 50% of cancers are associated with mutations to p53, the majority of which are located in the central DNA-binding domain. Here, we report molecular dynamics simulations of wild-type (WT) p53 and 20 different mutants, including a stabilized pseudo-WT mutant. Our findings indicate that p53 mutants tend to exacerbate latent structural-disruption tendencies, or vulnerabilities, already present in the WT protein, suggesting that it may be possible to develop cancer therapies by targeting a relatively small set of structural-disruption motifs rather than a multitude of effects specific to each mutant. In addition, α-sheet secondary structure formed in almost all of the proteins. α-Sheet has been hypothesized and recently demonstrated to play a role in amyloidogenesis, and its presence in the reported p53 simulations coincides with the recent re-consideration of cancer as an amyloid disease.
Insights
p53 protein mutations in cancer often worsen existing structural weaknesses. Targeting these common vulnerabilities, rather than individual mutations, may offer new cancer therapy strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- The p53 protein is a critical tumor suppressor, frequently mutated in approximately 50% of human cancers.
- Mutations in p53, primarily in its DNA-binding domain, lead to loss of function and contribute to cancer development.
Purpose of the Study:
- To investigate the structural dynamics of wild-type (WT) p53 and 20 mutants using molecular dynamics simulations.
- To identify common structural vulnerabilities in p53 mutants that could be targeted for therapeutic intervention.
- To explore the presence and implications of alpha-sheet secondary structures in p53 dynamics.
Main Methods:
- Utilized molecular dynamics simulations to analyze the structural behavior of wild-type p53 and 20 distinct mutants.
- Focused simulations on the central DNA-binding domain where most cancer-associated mutations occur.
- Examined the formation of secondary structures, specifically alpha-sheets, within the simulated p53 proteins.
Main Results:
- p53 mutants were found to amplify inherent structural weaknesses present in the wild-type protein.
- A common set of structural-disruption motifs was identified across various p53 mutants.
- Alpha-sheet secondary structures were observed in nearly all simulated p53 proteins, including WT and mutants.
Conclusions:
- Targeting shared structural vulnerabilities in p53 mutants, rather than individual mutations, presents a promising therapeutic avenue for cancer treatment.
- The prevalence of alpha-sheet structures in p53 simulations supports emerging theories linking cancer to amyloid diseases.
- Further research into p53 structural dynamics and alpha-sheet formation could lead to novel anti-cancer strategies.
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