Did you know that RNA (ribonucleic acid) has an anatomy? In fact, it has anatomical properties that are sometimes analogous to the human body; especially joints. Just like human joints such as the elbow, knee, and shoulder allow bending but only in certain directions; RNA has ‘joints’ (junctions) in its chemical structure, and these too allow flexing but only in certain directions. New research at the University of Michigan has isolated these RNA junctions and discovered that they determine much of the complex shapes that give RNA its ability to perform so many functions within a cell.
RNA in its many forms is loosely called ‘the messenger’ of DNA, but its scope of activity is broader. That’s why adding to the stock of knowledge about RNA can be so important; the impact can extend to treating cancer, correcting genetic defects, or improving metabolic health, just for example. In this case, the research team was interested not only in the way strands of RNA transformed into so many different structures, but also why certain drugs seemed to ‘freeze’ the structure.
What they found was that not only does RNA have junctions, which function like joints with specific possible positions, thus determining what possible geometric shapes the RNA can take, but also that the size of the drug molecules directly affect that shaping. Smaller drug molecules wedge themselves into the RNA junctions and prevent some folding or bending, leading to straighter RNA shapes. Larger molecules tend to freeze the shape into bends and folds.
“RNA is a very floppy molecule that often functions by binding to something else and then radically changing shape,” said Al-Hashimi, who is the Robert L. Kuczkowski Professor of Chemistry and a professor of biophysics [University of Michigan, USA]. These shape changes, in turn, trigger other processes or cascades of events, such as turning specific genes on or off.
Because of the RNA molecule’s mercurial nature, “you can’t really define it as having a single structure,” Al-Hashimi said. “It has many possible orientations, and different orientations are stabilized under different conditions, such as the presence of particular drug molecules.”
A major goal in structural biology and biophysics is to be able to predict not only the complex three-dimensional shapes that RNA assumes (which are dictated by the order of its nucleic acid building blocks), but also the various shapes RNA takes on after binding to other molecules such as proteins and small-molecule drugs. Further, researchers would like to be able to manipulate the 3-D structure and resulting activity of RNA by tweaking the drug molecules with which it interacts. But to do that, they need to understand the rules that govern the anatomy of RNA.
“With these findings, it now should be possible to predict gross features of RNA 3-D shapes based only on their secondary structure, which is far easier to determine than is 3-D structure,” Al-Hashimi said. “This will make it possible to gain insights into the 3-D shapes of RNA structures that are too large or complicated to be visualized by experimental techniques such as X-ray crystallography and NMR spectroscopy. The anatomical rules also provide a blueprint for rationally manipulating the structure and thus the activity of RNA, using small molecules in drug design efforts and also for engineering RNA sensors that change structure in user-prescribed ways.”