Since being discovered in 1993, microRNAs have gone on to win a Nobel Prize in Physiology or Medicine, thanks to private sector uptake with the COVID-19 vaccines that saved the world during the pandemic that emerged from Wuhan, China in early 2020. 

Errors in the manufacture of over 1,000 microRNAs can put us at risk for developmental disorders, cancer, or neurodegenerative disease and a new study looks at a molecular machine called Microprocessor (MP), which trims longer molecules called primary microRNAs (pri-miRNAs) - without cutting other kinds of RNA that resemble pri-miRNAs.

It has some help, because pri-miRNAs share a characteristic hairpin loop but the biological mystery is how MP knows which molecules to cut or how it manages to cut them correctly. Recent work used cryo-electron microscopy to capture freeze-frames of MP in action and could witness in stop-action fashion MP wrapping itself around five different pri-miRNAs, each with a distinct shape. In each image, a loop of RNA nestles within the same grooves of MP. They saw that the shape of MP differs depending on which pri-miRNA is in its grasp, leading the team to compare MP to an octopus armed with tentacle-like proteins.


Microprocessor as it interacts with differently shaped molecules like the primary microRNA pri-let-7a1 with a 180-degree rotation. Credit: Joshua-Tor lab/Cold Spring Harbor Laboratory

“The body of the octopus is sitting on the bottom of the hairpin, and the tentacles can go and kind of read the RNA. So, they make the same kind of interactions with the RNA," says Cold Spring Harbor Laboratory Professor Leemor Joshua-Tor, "but they can move with the RNA. The RNA basically dictates to the protein where it’s going to sit.”

That flexibility explains how MP can process so many different pri-miRNAs. Still, MP is choosy, leaving many hairpin-containing RNAs untouched. By seeing exactly how it interacts with different structures, the team is able to define key features that determine which RNAs MP will cut.