Allosteric and Dominant-Negative Effects in a p53 Core Heterotetramer

The tumor suppressor protein p53 is one of the most frequently mutated proteins in cancer cells and is a critical target for anticancer therapies. In the nucleus, the p53 core domain binds DNA response elements as a tetramer to regulate gene transcription. During early cancer development, mutant and wild-type p53 coexist and assemble into a heterotetramer. Experimental studies confirm that the R249S mutant exerts a dominant-negative effect on wild-type p53, but the underlying molecular mechanisms, particularly how allosteric inhibition mediates the effect, remain unclear. Here, we employed all-atom molecular dynamics simulations to investigate how the R249S mutation causes dominant-negative effects in the p53 heterotetramer. Our simulations show that the mutation drives the reorganization of interfacial interactions in the heterotetramer through multiple allosteric pathways. Interestingly, the wild-type subunit forms more stable interactions with the mutant subunit than it does with wild-type subunits to adapt to the negative effects induced by the mutation in the protein.