Conformational stability and dynamics of the cancer-associated isoform 133p53 are modulated by p53 peptides and p53-specific DNA
Conformational stability and dynamics of the cancer-associated isoform 133p53 are modulated by p53 peptides and p53-specific DNA
复制标题
癌症相关亚型 133p53 的构象稳定性和动态受 p53 肽和 p53 特异性 DNA 调节
DOI：
10.1096/fj.201801973r
复制
发表时间：
2019-03-01
期刊：
影响因子：
4.8
通讯作者：
Ma, Buyong
中科院分区：
文献类型：
--
作者：
Lei, Jiangtao;Qi, Ruxi;Ma, Buyong
p53 is a tumor suppressor protein that maintains genome stability, but its 133p53 and 160p53 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 133p53 and 160p53 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) p53, and the increased solvent exposure of their aggregation-triggering segment indicates their higher aggregation propensities than wt p53. We also found that 133p53 stability is modulable by peptide or DNA interactions. Adding a p53 peptide (derived from truncated p53 sequence 107-129) may help stabilize 133p53. Most importantly, our simulations of p53 isomer-DNA complexes indicate that 133p53 dimer, but not 160p53 dimer, could form a stable complex with p53-specific DNA, which is consistent with recent experiments. This study provides physicochemical insight into 133p53, 133p53-DNA complexes, 133p53'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 133p53 are modulated by p53 peptides and p53-specific DNA.
