If the cell were Gotham, viruses that mimic transfer RNAs (tRNAs) might qualify as Two Face, the supervillain who wreaks mayhem, right away or possibly later, depending on the outcome of a coin flip. This modus operandi, according to investigators based at the University of Colorado, does seem to be consistent with the actions of a viral RNA known to mimic the structure and behavior of cellular molecules.
These investigators had been aware that some plant-infecting RNA viruses have a “tRNA-like structure” (TLS) at the 3’ end of their genome that is aminoacylated—a feature that appears to be essential to the success of the virus. The investigators also pondered the example of “vtRNAs,” which are produced during gammaherpes virus infection, exported to the cytoplasm, packaged into the viral particle.
With either sort of virus, the structure-function relationships remained mysterious, and the investigators had few leads. Still, they asked questions: What are the structures of the tRNA-mimicking viral RNAs? What do they interact with? How tRNA-like are they? What undiscovered biological pathways might exist in both healthy and diseased cells that use tRNA-like molecules?
Some of these questions may soon be answered thanks to diligent detective work that has yielded new clues. This work was reported June 8 in Nature, in an article entitled “The structural basis of transfer RNA mimicry and conformational plasticity by a viral RNA.”
The investigators scrutinized examples from single-stranded positive-sense RNA viruses, a prototype being the TLS found at the 3′ end of the turnip yellow mosaic virus (TYMV). This TLS, the authors found, not only acts like a tRNA to drive aminoacylation of the viral genomic (g)RNA, it also interacts with other structures in the 3′ untranslated region of the gRNA, contains the promoter for negative-strand synthesis, and influences several infection-critical processes.
Using X-ray crystallography, the researchers, led by Jeffrey S. Kieft, Ph.D., visualized the molecule’s complex three-dimensional structure to high resolution. They observed that the viral RNA has a “two-faced” architecture: One face is a mimic of the cell’s RNA, the other face "diverges from tRNA and enables additional functionality." The divergent face probably gives the the viral RNA the ability to perform several tasks during infection. This type of behavior may be widespread; thus, the research carried out by Kieft’s team may apply to many different viruses.
Kieft’s team also determined that the viral DNA switched from function to function not by any means as simple as a coin flip, but rather through intramolecular interactions. These interactions allow the TLS to readily switch conformations. “The TLS is thus structured to perform several functions and interact with diverse binding partners,” wrote the authors. “And we demonstrate its ability to specifically bind to ribosomes.”
A release issued by the University of Colorado pointed out by enhancing our understanding of how a viral RNA can mimic other molecules and hijack a cell, the researchers may have contributed to ongoing efforts to develop treatments or vaccines against infectious disease. If medical interventions interfere with the viral RNA’s intramolecular mechanisms, the effect may resemble that of swiping Two Face’s coin mid-toss.