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-Structure paper
Title | Structural and functional basis of mammalian microRNA biogenesis by Dicer. |
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Journal, issue, pages | Mol Cell, Vol. 82, Issue 21, Page 4064-4079.e13, Year 2022 |
Publish date | Nov 3, 2022 |
Authors | David Zapletal / Eliska Taborska / Josef Pasulka / Radek Malik / Karel Kubicek / Martina Zanova / Christian Much / Marek Sebesta / Valeria Buccheri / Filip Horvat / Irena Jenickova / Michaela Prochazkova / Jan Prochazka / Matyas Pinkas / Jiri Novacek / Diego F Joseph / Radislav Sedlacek / Carrie Bernecky / Dónal O'Carroll / Richard Stefl / Petr Svoboda / |
PubMed Abstract | MicroRNA (miRNA) and RNA interference (RNAi) pathways rely on small RNAs produced by Dicer endonucleases. Mammalian Dicer primarily supports the essential gene-regulating miRNA pathway, but how it is ...MicroRNA (miRNA) and RNA interference (RNAi) pathways rely on small RNAs produced by Dicer endonucleases. Mammalian Dicer primarily supports the essential gene-regulating miRNA pathway, but how it is specifically adapted to miRNA biogenesis is unknown. We show that the adaptation entails a unique structural role of Dicer's DExD/H helicase domain. Although mice tolerate loss of its putative ATPase function, the complete absence of the domain is lethal because it assures high-fidelity miRNA biogenesis. Structures of murine Dicer•-miRNA precursor complexes revealed that the DExD/H domain has a helicase-unrelated structural function. It locks Dicer in a closed state, which facilitates miRNA precursor selection. Transition to a cleavage-competent open state is stimulated by Dicer-binding protein TARBP2. Absence of the DExD/H domain or its mutations unlocks the closed state, reduces substrate selectivity, and activates RNAi. Thus, the DExD/H domain structurally contributes to mammalian miRNA biogenesis and underlies mechanistical partitioning of miRNA and RNAi pathways. |
External links | Mol Cell / PubMed:36332606 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.81 - 6.21 Å |
Structure data | EMDB-14383, PDB-7yym: EMDB-14384, PDB-7yyn: EMDB-14387, PDB-7yz4: EMDB-14854, PDB-7zpi: EMDB-14855, PDB-7zpj: EMDB-14856, PDB-7zpk: |
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Keywords | RNA BINDING PROTEIN / endoribonuclease / dsRNA / complex / gene silencing / post-transcriptional / catalytic complex / cytoplasm / catalytic enzyme / RISC-loading complex / TARBP2 RNA BINDING PROTEIN |