Molecular mechanisms of functional rescue mediated by P53 tumor suppressor mutations
Autor: | Yu-Hong Tan, Vira Tretyachenko-Ladokhina, Xiang Ye, Wei Yang, Y. Morris Chen, Qiang Lu, Donald F. Senear, Ray Luo |
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Rok vydání: | 2009 |
Předmět: |
Models
Molecular Protein Folding Protein Conformation Static Electricity Mutant Biophysics Plasma protein binding Crystallography X-Ray Biochemistry Article law.invention Protein structure law Humans Suppressor mutation Genetics Chemistry Organic Chemistry Temperature DNA-binding domain Protein Structure Tertiary Amino Acid Substitution Mutation Suppressor Protein folding Salt bridge Protein Multimerization Tumor Suppressor Protein p53 Protein Binding |
Zdroj: | Biophysical Chemistry. 145:37-44 |
ISSN: | 0301-4622 |
Popis: | 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 beta-sandwich cancer mutants. |
Databáze: | OpenAIRE |
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