网络理论揭示了剪接体结构和动力学原理,bioRxiv - Biophysics

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网络理论揭示了剪接体结构和动力学原理
bioRxiv - Biophysics Pub Date : 2021-03-04 , DOI: 10.1101/2021.03.03.433650
Harpreet Kaur , Clarisse van der Feltz , Yichen Sun , Aaron A. Hoskins

Cryo-EM彻底改变了剪接体的结构生物学，现已确定了代表剪接周期大部分的数十种不同的剪接体结构。然而，由于拼接机械的极端组成和构象动力学以及随着拼接的进行而产生或消除的数千种分子间相互作用，这些结构的比较具有挑战性。我们已经使用网络理论通过从八个不同剪接体结构中发现的每个蛋白质-蛋白质，蛋白质-RNA和RNA-RNA相互作用构建基于结构的网络，来定量分析整个剪接周期中剪接因子的动态相互作用。我们的网络表明，包含剪接体的结构模块是高度动态的，在每个阶段，模块之间的因素都会振荡，同时网络的代数连接度也会发生较大变化。总体而言，剪接体的连接性集中在活性位点，部分原因是非球蛋白和NTC成分的贡献。在剪接过程中，剪接体的许多关键成分（包括Prp8和U2 snRNA）在特征向量和中间性中心均表现出较大的变化。其他因素仅在某些阶段显示出短暂的中间性中心，从而提出了通过短暂桥接否则连接不良的网络节点来调节拼接的机制。

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Network Theory Reveals Principles of Spliceosome Structure and Dynamics

Cryo-EM has revolutionized structural biology of the spliceosome and dozens of distinct spliceosome structures representing much of the splicing cycle have now been determined. However, comparison of these structures is challenging due to extreme compositional and conformational dynamics of the splicing machinery and the thousands of intermolecular interactions created or dismantled as splicing progresses. We have used network theory to quantitatively analyze the dynamic interactions of splicing factors throughout the splicing cycle by constructing structure-based networks from every protein-protein, protein-RNA, and RNA-RNA interaction found in eight different spliceosome structures. Our networks reveal that structural modules comprising the spliceosome are highly dynamic with factors oscillating between modules during each stage along with large changes in the algebraic connectivities of the networks. Overall, the spliceosome's connectivity is focused on the active site in part due to contributions from non-globular proteins and components of the NTC. Many key components of the spliceosome including Prp8 and the U2 snRNA exhibit large shifts in both eigenvector and betweenness centralities during splicing. Other factors show transiently high betweenness centralities only at certain stages thereby suggesting mechanisms for regulating splicing by briefly bridging otherwise poorly connected network nodes. These observations provide insights into the organizing principles of spliceosome architecture and provide a framework for comparative network analysis of similarly complex and dynamic macromolecular machines.

更新日期：2021-03-05

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