Structure of Human DROSHA

Cell. 2016 Jan 14;164(1-2):81-90. doi: 10.1016/j.cell.2015.12.019. Epub 2015 Dec 31.

Abstract

MicroRNA maturation is initiated by RNase III DROSHA that cleaves the stem loop of primary microRNA. DROSHA functions together with its cofactor DGCR8 in a heterotrimeric complex known as Microprocessor. Here, we report the X-ray structure of DROSHA in complex with the C-terminal helix of DGCR8. We find that DROSHA contains two DGCR8-binding sites, one on each RNase III domain (RIIID), which mediate the assembly of Microprocessor. The overall structure of DROSHA is surprisingly similar to that of Dicer despite no sequence homology apart from the C-terminal part, suggesting that DROSHA may have evolved from a Dicer homolog. DROSHA exhibits unique features, including non-canonical zinc-finger motifs, a long insertion in the first RIIID, and the kinked link between Connector helix and RIIID, which explains the 11-bp-measuring "ruler" activity of DROSHA. Our study implicates the evolutionary origin of DROSHA and elucidates the molecular basis of Microprocessor assembly and primary microRNA processing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • DEAD-box RNA Helicases / chemistry
  • DEAD-box RNA Helicases / metabolism
  • Evolution, Molecular
  • Humans
  • MicroRNAs / chemistry
  • MicroRNAs / metabolism*
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Nucleic Acid Conformation
  • Protein Folding
  • Protein Structure, Tertiary
  • RNA Processing, Post-Transcriptional*
  • RNA-Binding Proteins / metabolism
  • Ribonuclease III / chemistry*
  • Ribonuclease III / genetics
  • Ribonuclease III / metabolism
  • Sequence Alignment
  • Structural Homology, Protein

Substances

  • DGCR8 protein, human
  • MicroRNAs
  • RNA-Binding Proteins
  • DICER1 protein, human
  • DROSHA protein, human
  • Ribonuclease III
  • DEAD-box RNA Helicases