7XW3

Cryo-EM structure of an apo-form of human DICER

7XW3 の概要

• エントリーDOI: 10.2210/pdb7xw3/pdb
• EMDBエントリー: 33490
• 分子名称: Endoribonuclease Dicer (1 entity in total)
• 機能のキーワード: dicer, rnaseiii, rna-binding, micro-rna processing, gene regulation
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 218947.33

構造登録者

Lee, H.,Roh, S.-H. (登録日: 2022-05-26, 公開日: 2023-03-08, 最終更新日: 2024-07-03)

主引用文献

Lee, Y.Y.,Lee, H.,Kim, H.,Kim, V.N.,Roh, S.H.
Structure of the human DICER-pre-miRNA complex in a dicing state.
Nature, 615:331-338, 2023

PubMed Abstract: Dicer has a key role in small RNA biogenesis, processing double-stranded RNAs (dsRNAs). Human DICER (hDICER, also known as DICER1) is specialized for cleaving small hairpin structures such as precursor microRNAs (pre-miRNAs) and has limited activity towards long dsRNAs-unlike its homologues in lower eukaryotes and plants, which cleave long dsRNAs. Although the mechanism by which long dsRNAs are cleaved has been well documented, our understanding of pre-miRNA processing is incomplete because structures of hDICER in a catalytic state are lacking. Here we report the cryo-electron microscopy structure of hDICER bound to pre-miRNA in a dicing state and uncover the structural basis of pre-miRNA processing. hDICER undergoes large conformational changes to attain the active state. The helicase domain becomes flexible, which allows the binding of pre-miRNA to the catalytic valley. The double-stranded RNA-binding domain relocates and anchors pre-miRNA in a specific position through both sequence-independent and sequence-specific recognition of the newly identified 'GYM motif'. The DICER-specific PAZ helix is also reoriented to accommodate the RNA. Furthermore, our structure identifies a configuration of the 5' end of pre-miRNA inserted into a basic pocket. In this pocket, a group of arginine residues recognize the 5' terminal base (disfavouring guanine) and terminal monophosphate; this explains the specificity of hDICER and how it determines the cleavage site. We identify cancer-associated mutations in the 5' pocket residues that impair miRNA biogenesis. Our study reveals how hDICER recognizes pre-miRNAs with stringent specificity and enables a mechanistic understanding of hDICER-related diseases.

PubMed: 36813958
DOI: 10.1038/s41586-023-05723-3

実験手法

ELECTRON MICROSCOPY (4.04 Å)