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FASEB J. 2019 Mar;33(3):4225-4235. doi: 10.1096/fj.201801973R. Epub 2018 Dec 12.

Conformational stability and dynamics of the cancer-associated isoform Δ133p53β are modulated by p53 peptides and p53-specific DNA.

Author information

1
State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences-Ministry of Education, Department of Physics, Fudan University, Shanghai, China.
2
Department of Chemistry, Institute of Biomedical Sciences, Fudan University, Shanghai, China.
3
Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland, USA; and.
4
Department of Human Genetics and Molecular Medicine, Sackler Institute of Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Abstract

p53 is a tumor suppressor protein that maintains genome stability, but its Δ133p53β and Δ160p53β 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 Δ133p53β and Δ160p53β 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) p53β, and the increased solvent exposure of their aggregation-triggering segment indicates their higher aggregation propensities than wt p53. We also found that Δ133p53β 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 Δ133p53β dimer, but not Δ160p53β dimer, could form a stable complex with p53-specific DNA, which is consistent with recent experiments. This study provides physicochemical insight into Δ133p53β, Δ133p53β-DNA complexes, Δ133p53β'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 Δ133p53β are modulated by p53 peptides and p53-specific DNA.

KEYWORDS:

p53 aggregation; p53 response element; Δ160p53β cancer

PMID:
30540922
PMCID:
PMC6404584
[Available on 2020-03-01]
DOI:
10.1096/fj.201801973R

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