Conformational stability and dynamics of the cancer-associated isoform Δ133p53ß are modulated by p53 peptides and p53-specific DNA.

p53 is a tumor suppressor protein that maintains genome stability, but its Δ133p53ß and Δ160p53ß isoforms promote breast cancer cell invasion. The sequence truncations in the p53 core domain raise key questions related to their physicochemical properties, including structural stabilities, interaction mechanisms, and DNA-binding abilities. Herein, we investigated the conformational dynamics of Δ133p53ß and Δ160p53ß with and without binding to p53-specific DNA by using molecular dynamics simulations. We observed that the core domains of the 2 truncated isoforms are much less stable than wild-type (wt) p53ß, and the increased solvent exposure of their aggregation-triggering segment indicates their higher aggregation propensities than wt p53. We also found that Δ133p53ß stability is modulable by peptide or DNA interactions. Adding a p53 peptide (derived from truncated p53 sequence 107-129) may help stabilize Δ133p53. Most importantly, our simulations of p53 isomer-DNA complexes indicate that Δ133p53ß dimer, but not Δ160p53ß dimer, could form a stable complex with p53-specific DNA, which is consistent with recent experiments. This study provides physicochemical insight into Δ133p53ß, Δ133p53ß-DNA complexes, Δ133p53ß's pathologic mechanism, and peptide-based inhibitor design against p53-related cancers.-Lei, J., Qi, R., Tang, Y., Wang, W., Wei, G., Nussinov, R., Ma, B. Conformational stability and dynamics of the cancer-associated isoform Δ133p53ß are modulated by p53 peptides and p53-specific DNA.