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 affects a complete cycle of pre-miRNA recognition, stepwise endonuclease cleavage, and product release.

Epigenetics and Stem Cell Biology Laboratory National Institute of Environmental Health Sciences National Institutes of Health 111 T W Alexander Drive Research Triangle Park NC 27709 USA

RNA Therapeutics Institute University of Massachusetts Chan Medical School 368 Plantation Street Worcester MA 01605 USA

RNA Therapeutics Institute University of Massachusetts Chan Medical School 368 Plantation Street Worcester MA 01605 USA; Central European Institute of Technology Masaryk University Kamenice 5 Brno 62500 Czech Republic

RNA Therapeutics Institute University of Massachusetts Chan Medical School 368 Plantation Street Worcester MA 01605 USA; Howard Hughes Medical Institute University of Massachusetts Chan Medical School 368 Plantation Street Worcester MA 01605 USA

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JAMA Dermatol. 2022 Nov 1;158(11):1333. doi: 10.1001/jamadermatol.2022.3906. PubMed

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Mol Cell. 2022 Nov 3;82(21):4064-4079.e13. doi: 10.1016/j.molcel.2022.10.010. PubMed

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Dicer structure and function: conserved and evolving features

Structural and functional basis of mammalian microRNA biogenesis by Dicer