Multiscale simulation unravel the kinetic mechanisms of inflammasome assembly.
Multiscale simulation unravel the kinetic mechanisms of inflammasome assembly.
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DOI：
10.1016/j.bbamcr.2019.118612
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发表时间：
2019-11
期刊：
影响因子：
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通讯作者：
Zhaoqian Su;Yinghao Wu
中科院分区：
文献类型：
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作者：
Zhaoqian Su;Yinghao Wu
在先天免疫系统中，宿主防御外部病原体的入侵触发炎症反应。参与炎症通路的蛋白质通常被发现聚集成超分子寡聚体，称为“炎性体”，主要是通过它们属于死亡结构域超家族的结构域之间的同型相互作用。虽然已经知道了很多关于这些螺旋分子机器的形成，它们的组装动力学和每个域的结构之间的详细相关性仍然没有得到很好的理解。以接头分子ASC的PYD结构域形成的丝状体为实验系统，我们构建了一个新的多尺度模拟框架来研究炎性小体组装的动力学。我们发现，灯丝组装是一个多步骤，但高度合作的过程。此外，ASCPYD丝中结构域亚基之间存在三种类型的结合界面。多尺度模拟结果表明，结构域组装的动力学是植根于主要的蛋白质序列，它定义了通过三个结合界面的分子识别的能量。接口我起着更大的调节作用，比其他两个在调解组装的动力学和热力学。最后，我们的计算框架的效率，使我们能够设计突变体的系统规模和预测其对细丝组装的影响。总之，据我们所知，这是第一个模拟炎性小体组装时空过程的模拟方法。我们的工作是一个有用的补充，现有的一套实验技术来研究炎性小体在先天免疫系统中的功能。
In the innate immune system, the host defense from the invasion of external pathogens triggers the inflammatory responses. Proteins involved in the inflammatory pathways were often found to aggregate into supramolecular oligomers, called ‘inflammasome’, mostly through the homotypic interaction between their domains that belong to the death domain superfamily. Although much has been known about the formation of these helical molecular machineries, the detailed correlation between the dynamics of their assembly and the structure of each domain is still not well understood. Using the filament formed by the PYD domains of adaptor molecule ASC as a test system, we constructed a new multiscale simulation framework to study the kinetics of inflammasome assembly. We found that the filament assembly is a multi-step, but highly cooperative process. Moreover, there are three types of binding interfaces between domain subunits in the ASCPYDfilament. The multiscale simulation results suggest that dynamics of domain assembly are rooted in the primary protein sequence which defines the energetics of molecular recognition through three binding interfaces. Interface I plays a more regulatory role than the other two in mediating both the kinetics and the thermodynamics of assembly. Finally, the efficiency of our computational framework allows us to design mutants on a systematic scale and predict their impacts on filament assembly. In summary, this is, to the best of our knowledge, the first simulation method to model the spatial-temporal process of inflammasome assembly. Our work is a useful addition to a suite of existing experimental techniques to study the functions of inflammasome in innate immune system.