State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences-Ministry of Education, Department of Physics, Fudan University, Shanghai, China.
Department of Chemistry, Institute of Biomedical Sciences, Fudan University, Shanghai, China.
FASEB J. 2019 Mar;33(3):4225-4235. doi: 10.1096/fj.201801973R. Epub 2018 Dec 12.
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.
p53 是一种肿瘤抑制蛋白，可维持基因组稳定性，但它的 Δ133p53β 和 Δ160p53β 异构体可促进乳腺癌细胞的侵袭。p53 核心结构域中的序列缺失提出了与物理化学性质相关的关键问题，包括结构稳定性、相互作用机制和 DNA 结合能力。在此，我们通过分子动力学模拟研究了与 p53 特异性 DNA 结合或不结合时 Δ133p53β 和 Δ160p53β 的构象动力学。我们观察到，2 种截断异构体的核心结构域的稳定性远低于野生型（wt）p53β，其聚集触发片段的溶剂暴露增加表明它们的聚集倾向高于 wt p53。我们还发现 Δ133p53β 的稳定性可通过肽或 DNA 相互作用进行调节。添加 p53 肽（源自截断 p53 序列 107-129）可能有助于稳定 Δ133p53。最重要的是，我们对 p53 异构体-DNA 复合物的模拟表明，Δ133p53β 二聚体，但不是 Δ160p53β 二聚体，可与 p53 特异性 DNA 形成稳定的复合物，这与最近的实验结果一致。该研究为 Δ133p53β、Δ133p53β-DNA 复合物、Δ133p53β 的病理机制以及针对 p53 相关癌症的基于肽的抑制剂设计提供了物理化学见解。-雷静，齐锐，唐颖，王炜，魏刚，努斯林诺夫，马炳，癌症相关异构体 Δ133p53β 的构象稳定性和动力学受 p53 肽和 p53 特异性 DNA 的调节。
