Structure of the Dicer-2–R2D2 heterodimer bound to a small RNA duplex

In flies, Argonaute2 (Ago2) and small interfering RNA (siRNA) form an RNA-induced silencing complex to repress viral transcripts 1 . The RNase III enzyme Dicer-2 associates with its partner protein R2D2 and cleaves long double-stranded RNAs to produce 21-nucleotide siRNA duplexes, which are then loa...

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Bibliographic Details
Published in:Nature (London) Vol. 607; no. 7918; pp. 393 - 398
Main Authors: Yamaguchi, Sonomi, Naganuma, Masahiro, Nishizawa, Tomohiro, Kusakizako, Tsukasa, Tomari, Yukihide, Nishimasu, Hiroshi, Nureki, Osamu
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 14.07.2022
Nature Publishing Group
Subjects:
101/28
631/337/505
631/45/500
631/535/1258/1259
Animals
Argonaute 2 protein
Argonaute Proteins - metabolism
Asymmetry
Base Pairing
Binding sites
Cryoelectron Microscopy
DNA helicase
Drosophila melanogaster - chemistry
Drosophila melanogaster - genetics
Drosophila melanogaster - metabolism
Drosophila Proteins - chemistry
Drosophila Proteins - metabolism
Drosophila Proteins - ultrastructure
Electron microscopy
Enzymes
Humanities and Social Sciences
Insects
MicroRNAs
MicroRNAs - metabolism
Microscopy
miRNA
multidisciplinary
Mutation
Nucleotides
Protein Multimerization
Proteins
Ribonuclease III
Ribonuclease III - chemistry
Ribonuclease III - metabolism
Ribonuclease III - ultrastructure
Ribonucleic acid
RNA
RNA Helicases - chemistry
RNA Helicases - metabolism
RNA Helicases - ultrastructure
RNA Interference
RNA, Double-Stranded - chemistry
RNA, Double-Stranded - metabolism
RNA, Double-Stranded - ultrastructure
RNA, Small Interfering - chemistry
RNA, Small Interfering - metabolism
RNA, Small Interfering - ultrastructure
RNA-Binding Proteins - chemistry
RNA-Binding Proteins - metabolism
RNA-Binding Proteins - ultrastructure
RNA-induced silencing complex
RNA-Induced Silencing Complex - metabolism
RNA-mediated interference
Science
Science (multidisciplinary)
siRNA
ISSN:0028-0836, 1476-4687, 1476-4687
Online Access:Get full text
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Summary:In flies, Argonaute2 (Ago2) and small interfering RNA (siRNA) form an RNA-induced silencing complex to repress viral transcripts 1 . The RNase III enzyme Dicer-2 associates with its partner protein R2D2 and cleaves long double-stranded RNAs to produce 21-nucleotide siRNA duplexes, which are then loaded into Ago2 in a defined orientation 2 – 5 . Here we report cryo-electron microscopy structures of the Dicer-2–R2D2 and Dicer-2–R2D2–siRNA complexes. R2D2 interacts with the helicase domain and the central linker of Dicer-2 to inhibit the promiscuous processing of microRNA precursors by Dicer-2. Notably, our structure represents the strand-selection state in the siRNA-loading process, and reveals that R2D2 asymmetrically recognizes the end of the siRNA duplex with the higher base-pairing stability, and the other end is exposed to the solvent and is accessible by Ago2. Our findings explain how R2D2 senses the thermodynamic asymmetry of the siRNA and facilitates the siRNA loading into Ago2 in a defined orientation, thereby determining which strand of the siRNA duplex is used by Ago2 as the guide strand for target silencing. Cryo-electron microscopy structures of Drosophila Dicer-2–R2D2 complexes with and without small interfering RNA reveal how the RNA is presented to Argonaute in the correct orientation for viral gene silencing.
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ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-022-04790-2