Helicase-Dependent RNA Decay Illuminated by a Cryo-EM Structure of a Human Nuclear RNA Exosome-MTR4 Complex

Area of Science:

• Molecular Biology
• Structural Biology
• Biochemistry

Background:

• The RNA exosome is a crucial complex for RNA degradation.
• RNA helicases, like Mtr4, are known to interact with the exosome.
• Understanding the mechanism of RNA engagement and degradation is vital.

Purpose of the Study:

• To elucidate the mechanism by which the Mtr4 helicase interacts with the RNA exosome.
• To understand how Mtr4 unwinds structured RNA substrates to promote degradation.
• To determine the structural basis of Mtr4-exosome interaction.

Main Methods:

• Reconstitution of 14-subunit Mtr4-containing RNA exosomes from multiple species.
• Cryo-electron microscopy (cryo-EM) to determine the structure of the human exosome with stalled MTR4.
• Biochemical assays to assess substrate unwinding and degradation.

Main Results:

• Mtr4 helicase unwinds structured RNA substrates, promoting their degradation by the exosome.
• Cryo-EM structure reveals Mtr4 positioned atop the exosome core, with RNA in the central channel and DIS3 active site.
• MPP6 tethers Mtr4 to the exosome, while EXOSC10's catalytic module is displaced by RNA-engaged Mtr4.
• Competition for the exosome core suggests a mechanism for committing RNA to degradation.

Conclusions:

• Mtr4 plays a key role in targeting structured RNAs for degradation by the RNA exosome.
• The determined structure provides atomic-level insights into the Mtr4-exosome interaction and RNA processing.
• This mechanism ensures efficient and specific RNA degradation by the exosome complex.