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Structure paper

TitleStructural and functional basis of mammalian microRNA biogenesis by Dicer.
Journal, issue, pagesMol Cell, Vol. 82, Issue 21, Page 4064-4079.e13, Year 2022
Publish dateNov 3, 2022
AuthorsDavid 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 AbstractMicroRNA (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 linksMol Cell / PubMed:36332606 / PubMed Central
MethodsEM (single particle)
Resolution3.81 - 6.21 Å
Structure data

14383

7yym

EMDB-14383, PDB-7yym:
Mammalian Dicer in the "pre-dicing state" with pre-miR-15a substrate
Method: EM (single particle) / Resolution: 4.19 Å

14384

7yyn

EMDB-14384, PDB-7yyn:
Mammalian Dicer in the dicing state with pre-miR-15a substrate
Method: EM (single particle) / Resolution: 6.21 Å

14387

7yz4

EMDB-14387, PDB-7yz4:
Mouse endoribonuclease Dicer (composite structure)
Method: EM (single particle) / Resolution: 3.84 Å

14854

7zpi

EMDB-14854, PDB-7zpi:
Mammalian Dicer in the "dicing state" with pre-miR-15a substrate
Method: EM (single particle) / Resolution: 5.91 Å

14855

7zpj

EMDB-14855, PDB-7zpj:
Mammalian Dicer in the "pre-dicing state" with pre-miR-15a substrate and TARBP2 subunit
Method: EM (single particle) / Resolution: 3.81 Å

14856

7zpk

EMDB-14856, PDB-7zpk:
Mammalian Dicer in the "pre-dicing state" with pre-miR-15a substrate and TARBP2 subunit
Method: EM (single particle) / Resolution: 3.81 Å

Source
  • mus musculus (house mouse)
  • synthetic construct (others)
KeywordsRNA BINDING PROTEIN / endoribonuclease / dsRNA / complex / gene silencing / post-transcriptional / catalytic complex / cytoplasm / catalytic enzyme / RISC-loading complex / TARBP2 RNA BINDING PROTEIN

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