7yyn
Mammalian Dicer in the dicing state with pre-miR-15a substrate
Structural highlights
FunctionDICER_MOUSE Required for formation of the RNA induced silencing complex (RISC). Component of the RISC loading complex (RLC), also known as the micro-RNA (miRNA) loading complex (miRLC), which is composed of DICER1, EIF2C2/AGO2 and TARBP2. Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto EIF2C2/AGO2. EIF2C2/AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. Also cleaves double-stranded RNA to produce short interfering RNAs (siRNAs) which target the selective destruction of complementary RNAs (By similarity). Involved in cleaving double-stranded RNA in the RNA interference (RNAi) pathway. It produces 21 to 23 bp dsRNAs (siRNAs) which target the selective destruction of homologous RNAs. Publication Abstract from PubMedMicroRNA (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. Structural and functional basis of mammalian microRNA biogenesis by Dicer.,Zapletal D, Taborska E, Pasulka J, Malik R, Kubicek K, Zanova M, Much C, Sebesta M, Buccheri V, Horvat F, Jenickova I, Prochazkova M, Prochazka J, Pinkas M, Novacek J, Joseph DF, Sedlacek R, Bernecky C, O'Carroll D, Stefl R, Svoboda P Mol Cell. 2022 Nov 3;82(21):4064-4079.e13. doi: 10.1016/j.molcel.2022.10.010. PMID:36332606[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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