Microsecond molecular dynamics simulations reveal the allosteric regulatory mechanism of p53 R249S mutation in p53-associated liver cancer

Liu, Xianxian; Tian, Wenchao; Cheng, Jinying; Li, Dongmei; Liu, Tonggang; Zhang, Liguo

doi:10.1016/j.compbiolchem.2019.107194

Cited by 16 publications

(6 citation statements)

References 44 publications

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“…There have been several reports on the relationship between the type of GOF and the tumor spectrum in which they occur 46 , 47 . The results of the present study were consistent with previous reports, with a higher percentage of GOF with hotspot mutations, R249 in LIHC 48 , 49 and R273 in LGG 50 , 51 . As genes for which gene expression changes due to TP53 mutations contribute to cluster A1 and A2 classifications, 15 genes were extracted, consisting mainly of cell cycle-related genes and genes upstream of the p53 signaling pathway.…”

Section: Discussionsupporting

confidence: 93%

Different impacts of TP53 mutations on cell cycle-related gene expression among cancer types

Sasaki

Takahashi

Ouchi

et al. 2023

Sci Rep

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Functional properties caused by TP53 mutations are involved in cancer development and progression. Although most of the mutations lose normal p53 functions, some of them, gain-of-function (GOF) mutations, exhibiting novel oncogenic functions. No reports have analyzed the impact of TP53 mutations on the gene expression profile of the p53 signaling pathway across cancer types. This study is a cross-cancer type analysis of the effects of TP53 mutations on gene expression. A hierarchical cluster analysis of the expression profile of the p53 signaling pathway classified 21 cancer types into two clusters (A1 and A2). Changes in the expression of cell cycle-related genes and MKI67 by TP53 mutations were greater in cluster A1 than in cluster A2. There was no distinct difference in the effects between GOF and non-GOF mutations on the gene expression profile of the p53 signaling pathway.

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Section: Discussionsupporting

confidence: 93%

Different impacts of TP53 mutations on cell cycle-related gene expression among cancer types

Sasaki

Takahashi

Ouchi

et al. 2023

Sci Rep

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“…MD simulations and fragment screening have been utilized to uncover the Y220C-induced drug-binding surface and the destabilization mechanism of Y220C mutation on the p53 DBD structure . In addition, MD simulations in combination with Markov State Model analysis have been employed to investigate the effect of p53–MDM2 binding on the stability of p53–MDM2 complex. , These studies and others − greatly enhance our understanding of the molecular mechanism of p53 cancer-related mutations. However, they are focused on the DNA-free p53 systems, which cannot capture the effect of mutations on the p53–DNA binding affinity.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the Allosteric Mechanism of Four Cancer-related Mutations in the Disruption of p53-DNA Interaction

2021

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The p53 protein plays active roles in the physiological regulation of cell cycle as well as in cancer developments. In more than half of human cancers, the protein is inactivated by mutations located primarily in its DNA-binding domain (DBD), and some mutations located in the β-sandwich region of DBD are reported to decrease p53–DNA binding affinities. To understand the long-range correlation between p53 β-sandwich and DNA, and the allosteric mechanism of β-sandwich mutations in the disruption of p53–DNA interactions, we first identify three regions with a strong correlation with DNA based on microsecond molecular dynamics (MD) simulations of wild-type p53–DNA complex and then perform multiple MD simulations on four cancer-related mutants L145Q, P151S, Y220C, and G266R, which are located in these three regions. Our simulations show that these mutations allosterically destabilize the structural stability of the DNA-binding groove in p53 and disrupt the p53–DNA interactions. Network analyses reveal optimal correlation paths through which the mutation-induced allosteric signal passes to DNA, and the disturbance effect of these mutations on the global connectivity and dynamical correlation of the p53–DNA complex. This work paves the way for the in-depth understanding of the mutation-induced loss in p53’s DNA-recognition ability and the pathological mechanism of cancer development.

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“…随着两个对称二聚体之间接触点的增加, 四聚体与DNA的配合物更加稳定, 半衰期与亲和度有很大提高 [24] . Weinberg等 [22] 迄今为止, 相继出现了一系列关于p53-DBD 四聚体结构的实验结果 [14,20,[24][25][26] , 着重分析了四聚体分子中A-DNA, B-DNA和A-B之间的结构和相互作用. 对于DNA同侧A-D和B-C之间的蛋白-蛋白相互作用却鲜有分析.…”

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“…Cho等 [14] 得到的不对称的p53-DBD三体结构中, 由于处于DNA同侧的B, C链结合的是非一致序列, 导致B-C之间的相互作用非常微弱. 此外, 在Kitayner等 [20] 丧失 [16] 、局部结构域构象变化 [15,27] 和聚集特征 [28] .…”

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“…此外, 在Kitayner等 [20] 丧失 [16] 、局部结构域构象变化 [15,27] 和聚集特征 [28] . 对于p53-DBD寡聚结构的理论分析, Ma等 [29] 对 Cho等 [14] 得到的三体结构中 (PDB ID: 1TSR), A-B和B-C链组成的两种模型进行了分子动力学模拟. 结果表明, 相比于同侧B-C链形成的相互作用界面, 由于晶体堆积形成的A-B界面更有可能构成一个稳定的生物界面, 表现为A-B间有稳定的氢键和更强的结合能.…”

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Full-atomistic molecular dynamics analysis of p53 active tetramer

Zhou,

Geng,

Yan

2024

Acta Phys. Sin.

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p53 is a tumor suppressor protein that plays a crucial role in inhibiting cancer development and maintaining the genetic integrity. Within the cell nucleus, four p53 molecules form a stable tetrameric active structure through highly cooperative interactions, bind to DNA via its DNA-binding domain, and transcriptionally activate or inhibit their target genes. However, in most human tumor cells, there are numerous p53 mutations. The majority of these mutations are formed in the p53 DNA-binding domain, importantly, the p53 DNA-binding domain is critical for p53 to form the tetrameric active structures and to regulate the transcription of its downstream target genes.<br/>This study exploited the all-atom molecular dynamics simulations to investigate the mechanisms of interactions within the wild-type p53 tetramers. This study indicates that the symmetric dimers on either side of the DNA are stable ones, keep stable structures both before and after DNA bindings. The binding of two monomers on the same side of the DNA depends on proteinprotein interactions provided by two contact surfaces. DNA scaffold stabilizes the tetrameric active structure. Such interactions play a crucial role in helping the tetramer formation. This study clarifies the internal interactions and key residues within the p53 tetramer during dynamic processes, as well as the critical sites at various interaction interfaces. The findings of this study may provide a significant foundation for us to further understand the p53's anticancer mechanisms, to explore the effective cancer treatment strategies, and in near future, to develop the effective anti-cancer drugs.

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Microsecond molecular dynamics simulations reveal the allosteric regulatory mechanism of p53 R249S mutation in p53-associated liver cancer

Cited by 16 publications

References 44 publications

Different impacts of TP53 mutations on cell cycle-related gene expression among cancer types

Different impacts of TP53 mutations on cell cycle-related gene expression among cancer types

Unraveling the Allosteric Mechanism of Four Cancer-related Mutations in the Disruption of p53-DNA Interaction

Full-atomistic molecular dynamics analysis of p53 active tetramer

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