Cells use RNA strings to store information that is then translated into function in the form of proteins. Like DNA, RNA consists of a long string of only four different molecules, called bases. But RNA is more than just an information carrier — it can fold up into complex structures that then participate in chemical reactions themselves. However, unlike proteins, which are mostly static, the chaotic nature of RNA makes it difficult to handle or predict its shape. Now, Zhaoming Su and colleagues have developed a new method that tackles this problem by characterizing these RNAs at sub-nanometer resolution.

To do so, they combined existing methods of electron microscopy, chemical probing, and computer modelling. This allowed them to figure out the structure of the so-called Tetrahymena RNA, the first RNA ever discovered to participate in chemical reactions. In particular, this RNA glues two separate strings of other RNA together, resulting in a longer RNA string. Their method resolved how every single base on the RNA string is placed. Importantly, they could even see the bases that stretch out and reach across the whole structure, providing the bridges that define its overall shape. The speed of their method also enables them to look at the RNA at various stages in time, stacking these static images to make a movie that shows the whole mechanism.

Initially, this discovery means researchers can design artificial versions of Tetrahymena RNA to glue strings of RNA together more efficiently in a lab setting. Ultimately, beyond this specific RNA, this method can provide detailed enough models of other RNAs of interest to identify the position of every single base. With this information, scientists can make guided changes to the design and function of these RNAs, just as they have already been doing with proteins for decades.

The three lead authors are Zhaoming Su, now a PI at Sichuan University; Kaiming Zhang now at the University of Science and Technology of China in Hefei and both at the Department of Bioengineering and James H. Clark Center, Stanford University at the during the time of this work; and Kalli Kappel, now a postdoc at the Broad Institute of MIT and Harvard and a former graduate student in the Biophysics Program, Stanford University. Last authors are Rhiju Das, a PI in the Department of Biochemistry and Department of Physics at Stanford University and Wah Chiu, a professor in the Department of Bioengineering and James H. Clark Center at Stanford University

Managing Correspondent: Raphael Haslecker

Original Journal Article: https://doi.org/10.1038/s41586-021-03803-w

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