Noteworthy
The modified nucleoside pseudouridine (Ψ) has many reasons to be considered a star among the post-transcriptional RNA modifications. It was the first to be identified, in 1960. Incorporating it into mRNA vaccines was a big reason for their success. And it also shows up in numerous antibiotics. Now there's more. But first, what is Ψ anyways?
After transcription, specific enzymes – pseudouridine synthases – isomerize certain uridine residues in RNA such that the N-C bond between the base and the sugar is replaced with a C-C bond (as Janie described). This renders the sugar-base link much more resilient to degradation. In addition, the resulting new N-H in the sugar ring provides an extra hydrogen for hydrogen bonding. Consequently, Ψ can base pair with all other bases.
Secondary tRNA structure representations explaining how Ψ incorporation influences tRNA tertiary structure, mainly by elbow and junction regions stabilization (ASL - Anticodon Stem Loop). Adapted from source.
So, here's the news. A recent, large, and very thorough study combining cryoEM and computational modeling provides mechanistic detail on how Ψ serves to stabilize tRNA structure. In particular, the results reveal that the nearly universally conserved Ψ55 residue greatly stabilizes the tRNA by reinforcing the interactions between the two loops (the elbow) of the T and D arms of the molecule's clover leaf structure, as shown in the figure.
There's more. The authors also showed that replacing all uridines with Ψ-derivatives during in vitro transcription had a detrimental effect on the folding of tRNAs. Why is this important? In their own words: "Since current mRNA vaccines are completely modified by Ψ, these findings have far-reaching consequences for the potential use of folded RNA domains in next-generation RNA drugs. Our work certainly highlights that the specific incorporation of Ψ could be very beneficial for the stability of RNA domains, while saturating substitution could have unfavorable consequences."
("Noteworthy" is the new format for STC's Thursday posts. Please read our Jan 20, 2025 post outlining this and other changes in our blog.)
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