Molecular mechanisms of functional rescue mediated by P53 tumor suppressor mutations |
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Authors: | Yu-Hong Tan Y Morris Chen Xiang Ye Qiang Lu Vira Tretyachenko-Ladokhina Wei Yang Donald F Senear Ray Luo |
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Institution: | 1. Department of Molecular Biology and Biochemistry, University of California, Irvine, California, 92697;2. Department of Biomedical Engineering, University of California, Irvine, California, 92697;3. Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306 |
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Abstract: | We have utilized both molecular dynamics simulations and solution biophysical measurements to investigate the rescue mechanism of mutation N235K, which plays a key role in the recently identified global suppressor motif of K235/Y239/R240 in the human p53 DNA-binding domain (DBD). Previous genetic analysis indicates that N235K alone rescues five out of six destabilized cancer mutants. However, the solution biophysical measurement shows that N235K generates only a slight increase to the stability of DBD, implying a rescue mechanism that is not a simple additive contribution to thermodynamic stability. Our molecular simulations show that the N235K substitution generates two non-native salt bridges with residues D186 and E198. We find that the nonnative salt bridges, D186-K235 and E198-K235, and a native salt bridge, E171-R249, are mutually exclusive, thus resulting in only a marginal increase in stability as compared to the wild type protein. When a destabilized V157F is paired with N235K, the native salt bridge E171-R249 is retained. In this context, the non-native salt bridges, D186-K235 and E198-K235, produce a net increase in stability as compared to V157F alone. A similar rescue mechanism may explain how N235K stabilize other highly unstable β-sandwich cancer mutants. |
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Keywords: | p53 DNA-binding domain missense mutation suppressor mutation molecular dynamics protein stability |
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