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Structural mechanism of DNA-mediated Nanog–Sox2 cooperative interaction

机译：DNA介导的Nanog-Sox2协同相互作用的结构机理

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摘要

The efficiency of stem cell transcriptional regulation always depends on the cooperative association and expression of transcription factors (TFs). Among these, Oct4, Sox2, and Nanog play major roles. Their cooperativity is facilitated via direct protein–protein interactions or DNA-mediated interactions, yet the mechanism is not clear. Most biochemical studies have examined Oct4/Sox2 cooperativity, whereas few studies have evaluated how Nanog competes in the connection between these TFs. In this study, using computational models and molecular dynamics simulations, we built a framework representing the DNA-mediated cooperative interaction between Nanog and Sox2 and analyzed the plausible interaction factors experienced by Nanog because of Sox2, its cooperative binding partner. Comparison of a wild-type and mutant Nanog/Sox2 model with the Nanog crystal structure revealed the regulatory structural mechanism between Nanog/Sox2–DNA-mediated cooperative bindings. Along with the transactivation domains interaction, the DNA-mediated allosteric interactions are also necessary for Nanog cooperative binding. DNA-mediated Nanog–Sox2 cooperativity influences the protein conformational changes and a stronger interaction profile was observed for Nanog-Mut (L103E) in comparison with the Nanog-WT complex.
机译：干细胞转录调控的效率始终取决于转录因子（TFs）的协同关联和表达。其中，Oct4，Sox2和Nanog扮演主要角色。它们之间的直接作用是通过蛋白质间直接相互作用或DNA介导的相互作用而促进的，但机理尚不清楚。大多数生化研究都研究了Oct4 / Sox2的协同作用，而很少有研究评估Nanog如何竞争这些TF之间的连接。在这项研究中，我们使用计算模型和分子动力学模拟，建立了一个代表Nanog和Sox2之间DNA介导的协同相互作用的框架，并分析了Nanog由于其协同结合伙伴Sox2而经历的可能的相互作用因子。通过对具有Nanog晶体结构的野生型和突变型Nanog / Sox2模型进行比较，揭示了Nanog / Sox2-DNA介导的协同结合之间的调控结构机制。除反式激活域相互作用外，DNA介导的变构相互作用对于Nanog协同结合也是必需的。 DNA介导的Nanog-Sox2协同作用影响蛋白质的构象变化，与Nanog-WT复合物相比，Nanog-Mut（L103E）观察到更强的相互作用。

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