+検索条件
-Structure paper
タイトル | Structure of the human DICER-pre-miRNA complex in a dicing state. |
---|---|
ジャーナル・号・ページ | Nature, Vol. 615, Issue 7951, Page 331-338, Year 2023 |
掲載日 | 2023年2月22日 |
![]() | Young-Yoon Lee / Hansol Lee / Haedong Kim / V Narry Kim / Soung-Hun Roh / ![]() |
PubMed 要旨 | 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 ...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. |
![]() | ![]() ![]() |
手法 | EM (単粒子) |
解像度 | 3.04 - 4.04 Å |
構造データ | EMDB-33489, PDB-7xw2: EMDB-33490, PDB-7xw3: |
化合物 | ![]() ChemComp-CA: |
由来 |
|
![]() | GENE REGULATION/RNA / Dicer / RNaseIII / RNA-binding / micro-RNA processing / GENE REGULATION / GENE REGULATION-RNA complex |