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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Structure-function-rescue: the diverse nature of common p53 cancer mutants
1Centre for Protein Engineering, Medical Research Council Centre, Cambridge, UK. acj2@mrc-lmb.cam.ac.uk
Abstract:
The tumor suppressor protein p53 is inactivated by mutation in about half of all human cancers. Most mutations are located in the DNA-binding domain of the protein. It is, therefore, important to understand the structure of p53 and how it responds to mutation, so as to predict the phenotypic response and cancer prognosis. In this review, we present recent structural and systematic functional data that elucidate the molecular basis of how p53 is inactivated by different types of cancer mutation. Intriguingly, common cancer mutants exhibit a variety of distinct local structural changes, while the overall structural scaffold is largely preserved. The diverse structural and energetic response to mutation determines: (i) the folding state of a particular mutant under physiological conditions; (ii) its affinity for the various p53 target DNA sequences; and (iii) its protein-protein interactions both within the p53 tetramer and with a multitude of regulatory proteins. Further, the structural details of individual mutants provide the basis for the design of specific and generic drugs for cancer therapy purposes. In combination with studies on second-site suppressor mutations, it appears that some mutants are ideal rescue candidates, whereas for others simple pharmacological rescue by small molecule drugs may not be successful.
Insights
Tumor suppressor protein p53 mutations inactivate its function in many cancers. Understanding p53 structure and mutation responses aids cancer prognosis and drug design.
Area of Science:
- Molecular Biology
- Structural Biology
- Cancer Research
Background:
- The tumor suppressor protein p53 is crucial for preventing cancer.
- Mutations in p53 occur in approximately 50% of human cancers, primarily in its DNA-binding domain.
- Understanding these mutations is key to predicting cancer outcomes and developing therapies.
Purpose of the Study:
- To review recent structural and functional data on p53 inactivation by cancer mutations.
- To elucidate the molecular mechanisms underlying p53 dysfunction due to various mutations.
- To explore the implications of p53 structural changes for cancer drug development.
Main Methods:
- Review of recent structural data on p53 mutants.
- Systematic analysis of functional data from p53 mutants.
- Integration of structural and functional insights to understand mutation impact.
Main Results:
- Cancer-associated p53 mutants show diverse local structural changes, but the overall scaffold remains largely intact.
- Mutations affect p53's folding state, DNA binding affinity, and protein-protein interactions.
- Structural data provides a basis for designing targeted cancer therapies.
Conclusions:
- The specific structural and energetic responses to p53 mutations dictate their functional consequences.
- Some p53 mutants may be amenable to pharmacological rescue, while others may require different therapeutic strategies.
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