Understanding the Effects of Cancer-Associated Mutations in the Tumor Suppressor Protein p53: Structural Consequences of Mutations and Possible Ways of Rescuing Oncogenic Mutants
The tumor suppressor protein p53 is a key control in the cell cycle and plays a crucial role in the prevention of cancer development. It is mutated in approximately half of all human cancers and has, therefore, become an important target for the development of novel cancer therapies. Here, we review the structure of the protein, the effects of mutation and how they may be reversed. p53 has a highly complex domain organization consisting of structured regions combined with largely unstructured domains. Most cancer-associated mutations are located in the DNA-binding core domain of the protein. The molecular basis for the detrimental effect of these mutations has been elucidated by structural and biophysical studies. Whereas some mutations affect residues that make direct contact with target DNA, others induce structural perturbations that reduce the thermodynamic stability of the protein. Because p53 core domain is only marginally stable above body temperature, many cancer mutations not only induce local conformational changes but also cause global unfolding of the core domain under physiologic conditions. Novel therapeutic strategies aim, therefore, to develop chemical chaperones that help refold p53 mutants to their correct native structure. Valuable lessons can be learned from studies on so-called second-site suppressor mutations that reverse the effects of cancer mutations. These may provide a basis for the rational design of novel therapeutics.
KeywordsCore Domain Chemical Chaperone Heteronuclear Single Quantum Correlation Tetramerization Domain Color Insert
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