Elucidation of the conformational dynamics and assembly of Argonaute-RNA complexes by distinct yet coordinated actions of the supplementary microRNA.
Elucidation of the conformational dynamics and assembly of Argonaute-RNA complexes by distinct yet coordinated actions of the supplementary microRNA.
复制标题
通过补充 microRNA 的独特但协调的作用阐明 Argonaute-RNA 复合物的构象动力学和组装
DOI：
10.1016/j.csbj.2022.03.001
复制
发表时间：
2022
影响因子：
6
通讯作者：
Chai Z
中科院分区：
文献类型：
--
作者：
Zhuang H;Fan X;Ji D;Wang Y;Fan J;Li M;Ni D;Lu S;Li X;Chai Z
ArgAerte(AGO)蛋白是RNA诱导沉默复合体的核心，由microRNAs(MiRNAs)引导识别用于抑制的靶RNA。MiRNA-靶RNA识别最初是通过种子区域的配对形成的，而额外的补充配对可以增强目标识别，补偿种子失配。当在种子区和补充区配对时，miRNA长度的延长可以增强靶亲和力。然而，补充配对对AGO-RNA复合体的构象动力学和组装的影响机制尚不清楚。为了解决这个问题，我们对具有不同配对模式和miRNA长度的AGO-RNA复合体进行了大规模的分子动力学模拟。结果表明，额外的辅助配对不仅可以加强miRNA与靶RNA之间的相互作用，而且可以增加PAZ结构域的可塑性，增强AGO蛋白PAZ、PIWI、N结构域之间的连通性。这些结构域之间强大的社区网络收紧了AGO蛋白补充室的嘴，阻止了靶RNA从复合体中逃逸，并保护它免受溶剂水的攻击。重要的是，miRNA和靶RNA之间的内部较强匹配对可以补偿补充区边缘较弱的错配。这些发现为临床和实验设计miRNA模拟物和抗miRNAs提供了指导，并为进一步设计AGO蛋白作为基因调控领域的新工具开辟了道路。
Argonaute (AGO) proteins, the core of RNA-induced silencing complex, are guided by microRNAs (miRNAs) to recognize target RNA for repression. The miRNA–target RNA recognition forms initially through pairing at the seed region while the additional supplementary pairing can enhance target recognition and compensate for seed mismatch. The extension of miRNA lengths can strengthen the target affinity when pairing both in the seed and supplementary regions. However, the mechanism underlying the effect of the supplementary pairing on the conformational dynamics and the assembly of AGO–RNA complex remains poorly understood. To address this, we performed large-scale molecular dynamics simulations of AGO–RNA complexes with different pairing patterns and miRNA lengths. The results reveal that the additional supplementary pairing can not only strengthen the interaction between miRNA and target RNA, but also induce the increased plasticity of the PAZ domain and enhance the domain connectivity among the PAZ, PIWI, N domains of the AGO protein. The strong community network between these domains tightens the mouth of the supplementary chamber of AGO protein, which prevents the escape of target RNA from the complex and shields it from solvent water attack. Importantly, the inner stronger matching pairs between the miRNA and target RNA can compensate for weaker mismatches at the edge of supplementary region. These findings provide guidance for the design of miRNA mimics and anti-miRNAs for both clinical and experimental use and open the way for further engineering of AGO proteins as a new tool in the field of gene regulation.
登录
查看更多内容
影响因子：
5.8
作者：
Eargle, John;Luthey-Schulten, Zaida
通讯作者：
Luthey-Schulten, Zaida
影响因子：
64.5
作者：
Elkayam E;Kuhn CD;Tocilj A;Haase AD;Greene EM;Hannon GJ;Joshua-Tor L
通讯作者：
Joshua-Tor L
影响因子：
64.5
作者：
Helwak A;Kudla G;Dudnakova T;Tollervey D
通讯作者：
Tollervey D
DOI：
10.1016/j.csbj.2019.12.003
发表时间：
2020-01-01
影响因子：
6
作者：
Gonzalez-Rivera, Juan C.;Orr, Asuka A.;Tamamis, Phanourios
通讯作者：
Tamamis, Phanourios
影响因子：
3.7
作者：
Ali Hassan NZ;Mokhtar NM;Kok Sin T;Mohamed Rose I;Sagap I;Harun R;Jamal R
通讯作者：
Jamal R