Turning tRNA upside down: When aminoacylation is not a prerequisite to protein synthesis.

Abstract

In the first 20 years since their discovery, the aminoacyl-tRNA synthetases (aaRS) were considered purely for their roles in protein synthesis. Each aaRS links its cognate amino acid to one of the tRNAs bearing the appropriate anticodon trinucleotides before decoding and translation by the ribosome. The accuracy of this aminoacylation reaction depends on the ability of each aaRS to select its cognate substrates from pools of chemically similar amino acid and tRNA substrates, which in turn relies on the presence of highly specific binding sites for both nucleic acids and amino acids. In the original formulation of Crick's adaptor hypothesis, each amino acid and corresponding tRNA was envisioned to match a single cognate aaRS, but this view has largely been over-turned (1). Large-scale sequencing efforts revealed that many genomes of extant organisms contain both duplications of full-length tRNA synthetases, as well as aaRS-like proteins, which are evolutionarily conserved fragments reiterating functional domains from many known synthetases (2, 3). Functions have been deduced for only a small fraction of these proteins, and, in most cases, it is the catalytic core domains that have been recruited for a variety of new roles. These include roles in amino acid biosynthesis (4, 5), DNA replication processivity (6), and protein synthesis quality control (7, 8). The paper by Salazar et al. (9) in this issue of PNAS adds to this list by describing how the glutamyl-tRNA synthetase (GluRS) paralog YadB attaches glutamate to queuosine, generating a hypermodified nucleoside at the first anticodon position of tRNAAsp. This surprising finding provides a further dramatic illustration of the catalytic and RNA recognition versatility of the class I aaRS catalytic fold, and it implies that tRNA modifications might be more widespread than previously anticipated, owing to their chemical lability. The function of YadB, which …