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研究揭示Dicer-2–R2D2异二聚体与小RNA双链结合的结构
2022-06-30 19:55
来源：小柯机器人

日本东京大学Osamu Nureki、Hiroshi Nishimasu等研究人员合作揭示Dicer-2–R2D2异二聚体与小RNA双链结合的结构。相关论文于2022年6月29日在线发表于国际学术期刊《自然》。

研究人员表示，在果蝇中，Argonaute2（Ago2）和小干扰RNA（siRNA）形成一个RNA诱导的沉默复合物来抑制病毒转录物。RNase III酶Dicer-2与它的伙伴蛋白 R2D2 结合，切割长的双链 RNA，产生21个核苷酸的siRNA双链，然后以确定的方向装入Ago2中。
 
研究人员报告了Dicer-2-R2D2和Dicer-2-R2D2-siRNA复合体的冷冻电镜结构。R2D2与Dicer-2的螺旋酶结构域和中心连接体相互作用，从而抑制Dicer-2对microRNA前体的错误加工。值得注意的是，这个结构代表了siRNA加载过程中的链选择状态，并揭示了R2D2不对称地识别了具有较高碱基配对稳定性的siRNA双链一端，而另一端暴露在溶剂中，可被Ago2接触。
 
这些研究结果解释了R2D2如何感知siRNA的热力学不对称性，并促进siRNA以确定的方向加载到Ago2中，从而决定siRNA双链的哪条链被Ago2用作目标沉默的引导链。
 
附：英文原文
 
Title: Structure of the Dicer-2–R2D2 heterodimer bound to a small RNA duplex

Author: Yamaguchi, Sonomi, Naganuma, Masahiro, Nishizawa, Tomohiro, Kusakizako, Tsukasa, Tomari, Yukihide, Nishimasu, Hiroshi, Nureki, Osamu

Issue&Volume: 2022-06-29

Abstract: In flies, Argonaute2 (Ago2) and small interfering RNA (siRNA) form an RNA-induced silencing complex to repress viral transcripts1. 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 orientation2–5. 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.

DOI: 10.1038/s41586-022-04790-2

Source: https://www.nature.com/articles/s41586-022-04790-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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