Striking new videos show how RNA – the genetic molecule that tells cells how to build proteins – is entangled in insane nodes as they form, only to disrupt it at the last second and in a way that has surprised scientists.
The high-resolution videos depict a reflective conglomeration of nucleotides, the building blocks of RNA; as the single strand of RNA lengthens, these nucleotides dance and twist into different three-dimensional shapes, wrapping first in one conformation and then in another. Once fully assembled, the RNA takes its final form, determining how it can communicate with other molecules and proteins in the cell.
But along the way, the RNA can get caught in ‘knots’ that need to be undone to reveal this final shape.
“So the RNA has to come out of it,” said study author Julius Lucks, associate professor of chemical and biological engineering and a member of the Center for Synthetic Biology at Northwestern University. The RNA will not function properly if it remains trapped in the wrong node, which means that it is a node that gets in the way of the final shape. “What was surprising was how it came out of the trap. … It was only discovered when we had high-resolution videos.”
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In the new study, which appeared in the journal on January 15 Molecular cell, Lucks and his colleagues generated their videos from RNA using experimental data and a computer algorithm. The aim was to zoom in on how RNA forms, both to better understand basic cell biology and to pave the way for better treatments for RNA-related diseases.
In the experiments, the team used a specific type of RNA, called signal recognition particle (SNP) RNA, an evolutionary ancient molecule found in all living things. They use this RNA as a model as it has a fundamental function in many types of cells.
To zoom in on how selle to build this RNA, the team used chemicals to interrupt the construction process. When new nucleotides were added to the RNA, the researchers paused and then recorded how the nucleotides interacted with others in the series and what shapes all formed together. By capturing the data of many individual RNA molecules, the team developed snapshots of how RNA generally constructs itself.
These screenshots served as individual frames in their latest videos of RNA formation. This is where the computer model came in. The algorithm merged the individual frames into minifilms and filled the gaps between frames with the most likely nucleotide interactions. In these videos, the team noticed how the RNA became entangled in intricate knots that would render the entire molecule useless if it were bound.
“It folds in this state of mind, and it stays there,” Lucks said. SNP RNA is meant to form into a characteristic “hairpin-like” shape, and these traps seem to get in the way. But as more nucleotides are added to the series, the new nucleotides swing in to unravel the knot by displacing the jumbled nucleotides.
“That last little nucleotide is like a trigger” that enables the entire RNA to get in the right shape, Lucks said. Think of the last fold in an origami project, which suddenly transforms a curly piece of paper into a lovely butterfly. In the videos, the nucleotides highlighted in dark purple knot themselves up, and the dark pink nucleotides help to liberate them, Lucks noted.
Learning how RNA gets mixed up and unraveled is the key to understanding how cells function and how proteins form; the research can also help address diseases where RNA is not functioning properly or can form a specific protein, such as spinal muscle atrophy, and infectious diseases such as COVID-19 caused by RNA viruses, according to a statement.
A big question is whether RNA can mostly unravel itself from these nodes, and whether it sometimes needs proteins to facilitate the process. It is possible that some proteins act as so-called ‘RNA chaperones’ and help shape the molecule into the final form,’ Lucks said. He added that it could be a combination of both, although it is currently speculative.
Originally published on Live Science.