Substrate-specific structural rearrangements of human Dicer

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• Dicer is crucial for RNA interference, processing double-stranded RNAs (dsRNAs) into small regulatory RNAs.
• Human Dicer generates short interfering RNAs (siRNAs) from dsRNAs and microRNAs (miRNAs) from hairpin precursors.
• Pre-miRNAs are typically processed faster than pre-siRNAs by Dicer in vitro.

Purpose of the Study:

• To investigate the structural basis for human Dicer's substrate preference.
• To understand how Dicer distinguishes between different RNA precursors.

Main Methods:

• Electron microscopy (EM) of Dicer-RNA complexes.
• Single-particle analysis to determine complex structures.

Main Results:

• Dicer traps pre-siRNA substrates in a nonproductive conformation.
• Dicer undergoes structural changes upon binding pre-miRNAs or dsRNA-binding proteins.
• These changes facilitate productive substrate engagement in the catalytic channel.

Conclusions:

• RNA structure and cofactors dictate human Dicer's substrate recognition.
• Enzyme conformation changes are key to processing efficiency for siRNAs and miRNAs.