A new study led by Northwestern University develops the mystery of how RNA molecules fold themselves to fit into cells and perform specific functions. The findings could potentially break an obstacle to the understanding and development of treatments for RNA-related diseases, including spinal muscle atrophy and perhaps even the new coronavirus.
“RNA folding is a dynamic process that is essential for life,” said Julius B. Lucks of Northwestern, who led the study. “RNA is a very important piece of diagnostic and therapeutic design. The more we know about RNA folding and complexity, the better we can design treatments.”
Using data from RNA folding experiments, the researchers produced the very first data-driven films of how RNA folds as made by cellular machinery. By watching their videos of this fold, the researchers discover that RNA often folds in surprising, perhaps unintuitive ways, such as tying itself in knots – and then immediately loosening it to reach its final structure.
“Folding takes place more than ten million times per second in your body,” Lucks said. “It happens every time a gene is expressed in a cell, yet we know so little about it. Our films allow us to finally see folding happen for the first time.”
The research will be published in the journal on January 15 Molecular cell.
Lucks is an associate professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and a member of Northwestern’s Center for Synthetic Biology. He co-led the work with Alan Chen, an associate professor of chemistry at the University of Albany.
Although there are videos of RNA folding, the computer models it generates are full of approaches and assumptions. Lucks’ team has developed a technology platform that records data from RNA folds while the RNA is being created. His group then uses computational tools to extract and organize the data, revealing points where the RNA folds and what happens after it is folded. Angela Yu, a former student of Lucks, entered this data into computer models to generate accurate videos of the folding process.
“The information we give to the algorithms helps the computer models to correct themselves,” Lucks said. “The model makes accurate simulations that match the data.”
Lucks and his associates used this strategy to form the fold of an RNA called SRP, an ancient RNA found in all kingdoms of life. The molecule is known for its characteristic hairpin shape. When they watched the videos, the researchers discovered that the molecule binds itself in a knot and is released very quickly. Then it suddenly falls into the correct hairpin-like structure using an elegant folding track called toehold-mediated strand displacement.
“As far as we know, it’s never been seen in the wild,” Lucks said. “We think the RNA evolved to detach itself from nodes, because if nodes persist, it can make the RNA dysfunctional. The structure is so vital to life that it had to evolve to find a way out of a knot to come. “
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The study, “Computationally reconstructing cotranscriptional RNA folding path from experimental data reveals rearrangement of non-native folding intermediaries,” was supported by the National Institutes of Health (grant numbers T32GM083937, 1DP2GM110838 and GM120582), the National Science Foundation, and 19 grants5181877 ) and the Searle Funds at The Chicago Community Trust.
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