Structural insights into dsRNA processing by Drosophila Dicer-2–Loqs-PD

Shichen Su, Jia Wang, Ting Deng, Xun Yuan, Jinqiu He, Nan Liu, Xiaomin Li, Ying Huang, Hong-Wei Wang () and Jinbiao Ma ()
Additional contact information
Shichen Su: Fudan University
Jia Wang: Tsinghua University
Ting Deng: Fudan University
Xun Yuan: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
Jinqiu He: Fudan University
Nan Liu: Tsinghua University
Xiaomin Li: Tsinghua University
Ying Huang: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
Hong-Wei Wang: Tsinghua University
Jinbiao Ma: Fudan University

Nature, 2022, vol. 607, issue 7918, 399-406

Abstract: Abstract Small interfering RNAs (siRNAs) are the key components for RNA interference (RNAi), a conserved RNA-silencing mechanism in many eukaryotes1,2. In Drosophila, an RNase III enzyme Dicer-2 (Dcr-2), aided by its cofactor Loquacious-PD (Loqs-PD), has an important role in generating 21 bp siRNA duplexes from long double-stranded RNAs (dsRNAs)3,4. ATP hydrolysis by the helicase domain of Dcr-2 is critical to the successful processing of a long dsRNA into consecutive siRNA duplexes5,6. Here we report the cryo-electron microscopy structures of Dcr-2–Loqs-PD in the apo state and in multiple states in which it is processing a 50 bp dsRNA substrate. The structures elucidated interactions between Dcr-2 and Loqs-PD, and substantial conformational changes of Dcr-2 during a dsRNA-processing cycle. The N-terminal helicase and domain of unknown function 283 (DUF283) domains undergo conformational changes after initial dsRNA binding, forming an ATP-binding pocket and a 5′-phosphate-binding pocket. The overall conformation of Dcr-2–Loqs-PD is relatively rigid during translocating along the dsRNA in the presence of ATP, whereas the interactions between the DUF283 and RIIIDb domains prevent non-specific cleavage during translocation by blocking the access of dsRNA to the RNase active centre. Additional ATP-dependent conformational changes are required to form an active dicing state and precisely cleave the dsRNA into a 21 bp siRNA duplex as confirmed by the structure in the post-dicing state. Collectively, this study revealed the molecular mechanism for the full cycle of ATP-dependent dsRNA processing by Dcr-2–Loqs-PD.

Date: 2022
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DOI: 10.1038/s41586-022-04911-x

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