A new study led by Northwestern University reveals the mystery of how RNA molecules fold to fit inside cells and perform specific functions. The findings could destroy a barrier to understanding and developing treatments for RNA-related diseases, including spinal muscle atrophy and perhaps even the new coronavirus.
“RNA folding is a dynamic process that is fundamental to life,” said Julius B. Lucks of Northwestern, who led the study. RNA is a really important piece of diagnostic and therapeutic design. The more we know about RNA folding and complexities, the better we can design treatments.
Using data from RNA folding experiments, the researchers generated the first films based on data about how RNA folds as it is made by cellular machines. Following their videos on this bending, the researchers found that RNA often folds in surprising, perhaps unintuitive, ways, such as tying in nodes – and then immediate release to reach its final structure.
“Folding takes place in your body more than 10 patrillion times per second,” 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 watch it 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 the McCormick School of Engineering in Northwestern and a member of the Center for Synthetic Biology in Northwestern. He led the work with Alan Chen, an associate professor of chemistry at the University of Albany.
Although there are RNA-folding videos, the computer models that generate them are full of approximations and assumptions. Lucks’ team has developed a technology platform that captures data on RNA folding as RNA is made. His group then uses computational tools to extract and organize the data, revealing the points where the RNA folds and what happens after it folds. Angela Yu, a former student of Lucks, entered this data into computer models to generate accurate videos of the folding process.
“The information we provide to algorithms helps computer models to correct themselves,” Lucks said. “The model performs accurate simulations that are consistent with the data.”
Lucks and his collaborators used this strategy to model the folding of an RNA called SRP, an ancient RNA found in all realms of life. The molecule is well known for the shape of the hairpin signature. When they watched the videos, the researchers found that the molecule binds to a node and unbinds very quickly. Then, it is suddenly overturned into the correct, needle-like structure, using an elegant foldable path called the toehold-mediated displacement of the thread.
“As far as we know, this has never been seen in nature,” Lucks said. “We believe that RNA has evolved to detach from nodes, because if the nodes persist, it can make RNA dysfunctional. The structure is so essential to life that it had to evolve to find a way out of a node. . “
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The study, “Computerized Reconstruction of Co-Transcriptional RNA Folding Pathways from Experimental Data Reveals Rearrangement of Non-Native Folding Intermediates,” was supported by the National Institutes of Health (assignment numbers T32GM083937, 1DP2GM110838 and GM120582), National Science Foundation assignment numbers MCB1651877 and 1914567) and Searle Funds at the Chicago Community Trust.
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