Structural mechanism of R2D2 and Loqs-PD synergistic modulation on DmDcr-2 oligomers.
Structural mechanism of R2D2 and Loqs-PD synergistic modulation on DmDcr-2 oligomers.
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DOI：
10.1038/s41467-023-40919-1
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发表时间：
2023-08-26
影响因子：
16.6
通讯作者：
Wang, Jia
中科院分区：
文献类型：
--
作者：
Deng, Ting;Su, Shichen;Yuan, Xun;He, Jinqiu;Huang, Ying;Ma, Jinbiao;Wang, Jia
小干扰RNA是RNA干扰的关键组分，RNA干扰是许多真核生物中保守的RNA沉默或病毒防御机制。在果蝇中，Dicer-2（DmDcr-2）介导的RNAi途径在防御病毒感染和保护基因组完整性方面发挥重要作用。在siRNA的成熟过程中，两种辅因子可以调节DmDcr-2的功能：dsRNA加工所需的Loqs-PD和随后将siRNA加载到效应物Ago 2中以形成RISC复合物所必需的R2D2。然而，由于缺乏结构信息，目前还不清楚R2D2和Loqs-PD是否同时影响DmDcr-2的功能。在这里，我们提出了几个cryo-EM结构的DmDcr-2/R2D2/Loqs-PD复合物结合到不同长度的dsRNA的解旋酶结构域。这些结构表明R2D2和Loqs-PD可以与DmDcr-2的不同区域结合，而不会相互干扰。此外，冷冻电镜结果表明，这些复合物可以形成大的低聚物和组装成纤维。这些低聚物的形成和解聚与ATP水解有关。这些发现为深入了解siRNA加工过程中DmDcr-2及其辅因子的结构机制提供了依据。R2D2和Loqs-PD是果蝇Dicer-2（DmDcr-2）的辅因子，其产生siRNA。在这里，作者报告了DmDcr-2/R2D2/Loqs-PD与dsRNA的冷冻电镜结构，表明这些复合物可以形成寡聚体并组装成纤维。
Small interference RNAs are the key components of RNA interference, a conserved RNA silencing or viral defense mechanism in many eukaryotes. In Drosophila melanogaster, Dicer-2 (DmDcr-2)-mediated RNAi pathway plays important roles in defending against viral infections and protecting genome integrity. During the maturation of siRNAs, two cofactors can regulate DmDcr-2’s functions: Loqs-PD that is required for dsRNA processing, and R2D2 that is essential for the subsequent loading of siRNAs into effector Ago2 to form RISC complexes. However, due to the lack of structural information, it is still unclear whether R2D2 and Loqs-PD affect the functions of DmDcr-2 simultaneously. Here we present several cryo-EM structures of DmDcr-2/R2D2/Loqs-PD complex bound to dsRNAs with various lengths by the Helicase domain. These structures revealed that R2D2 and Loqs-PD can bind to different regions of DmDcr-2 without interfering with each other. Furthermore, the cryo-EM results demonstrate that these complexes can form large oligomers and assemble into fibers. The formation and depolymerization of these oligomers are associated with ATP hydrolysis. These findings provide insights into the structural mechanism of DmDcr-2 and its cofactors during siRNA processing. R2D2 and Loqs-PD are cofactors of Drosophila Dicer-2 (DmDcr-2), which generates siRNAs. Here the authors report the cryo-EM structures of DmDcr-2/R2D2/Loqs-PD with dsRNAs showing that these complexes can form oligomers and assemble into fibers.
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影响因子：
16
作者：
Jouravleva, Karina;Golovenko, Dmitrij;Demo, Gabriel;Dutcher, Robert C.;Hall, Traci M. Tanaka;Zamore, Phillip D.;Korostelev, Andrei A.
通讯作者：
Korostelev, Andrei A.
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
16.8
作者：
通讯作者：
--
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
11.4
作者：
Lee, Y;Hur, I;Kim, VN
通讯作者：
Kim, VN