Structural basis of microRNA biogenesis by Dicer-1 and its partner protein Loqs-PB.
Structural basis of microRNA biogenesis by Dicer-1 and its partner protein Loqs-PB.
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Dicer-1及其伴生蛋白Loqs-PB发生microRNA的结构基础。
DOI：
10.1016/j.molcel.2022.09.002
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发表时间：
2022-11-03
期刊：
影响因子：
16
通讯作者：
Korostelev, Andrei A.
中科院分区：
文献类型：
--
作者：
Jouravleva, Karina;Golovenko, Dmitrij;Demo, Gabriel;Dutcher, Robert C.;Hall, Traci M. Tanaka;Zamore, Phillip D.;Korostelev, Andrei A.
在动植物中，DICER酶与双链RNA结合结构域(DsRBD)蛋白合作，将前体-microRNAs(前miRNAs)转化为miRNA双链。我们报道了果蝇DICER-1的六种冷冻EM结构，这些结构展示了DICER-1及其合作伙伴Loqs-PB如何(1)在结合前miRNA之前，(2)结合之后并处于催化活性状态，(3)在切割前miRNA的一只手臂之后，以及(4)在完全切割和初始产物释放之后。我们的重建表明，前miRNA结合了一种罕见的开放构象的Dird-1·Loqs-PB异源二聚体。Dice-1 dsRBD和三个Loqs-PB dsRBD在前miRNA周围形成了一条紧凑的带子，扭曲了RNA螺旋，将剪裁的磷酸二酯键放置在RNaseIII的活性部位。Pre-miRNA裂解使dsRBD移位，部分关闭DICER-1，可能促进产物释放。我们的数据建议了一个模型，说明Dice-1·Loqs-PB复合体如何影响前miRNA识别、逐步内切酶切割和产物释放的完整周期。六个高分辨率的低温EM结构揭示了DICER-1-哺乳动物的苍蝇同源物-如何与其双链RNA结合结构域伙伴loquacous PB(Loqs-PB)合作，验证真正的microRNA前体(前miRNAs)，并催化将前miRNA逐步加工成准备被装载到ArgAerte蛋白质中的microRNA/microRNA*双链。
In animals and plants, Dicer enzymes collaborate with double-stranded RNA-binding domain (dsRBD) proteins to convert precursor-microRNAs (pre-miRNAs) into miRNA duplexes. We report six cryo-EM structures of Drosophila Dicer-1 that show how Dicer-1 and its partner Loqs-PB cooperate (1) before binding pre-miRNA, (2) after binding and in a catalytically competent state, (3) after nicking one arm of the pre-miRNA, and (4) following complete dicing and initial product release. Our reconstructions suggest that pre-miRNA binds a rare, open conformation of the Dicer-1•Loqs-PB heterodimer. The Dicer-1 dsRBD and three Loqs-PB dsRBDs form a tight belt around the pre-miRNA, distorting the RNA helix to place the scissile phosphodiester bonds in the RNase III active sites. Pre-miRNA cleavage shifts the dsRBDs and partially closes Dicer-1, which may promote product release. Our data suggest a model for how the Dicer-1•Loqs-PB complex effects a complete cycle of pre-miRNA recognition, stepwise endonuclease cleavage, and product release. Six high-resolution cryo-EM structures reveal how Dicer-1—the fly homolog of mammalian Dicer—collaborates with its double-stranded RNA-binding domain partner Loquacious-PB (Loqs-PB) to validate authentic microRNA precursors (pre-miRNAs) and to catalyze the stepwise processing of a pre-miRNA into a microRNA/microRNA* duplex ready to be loaded into an Argonaute protein.
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