Charging the code - tRNA modification complexes.

All types of cellular RNAs are post-transcriptionally modified, constituting the so called 'epitranscriptome'. In particular, tRNAs and their anticodon stem loops represent major modification hotspots. The attachment of small chemical groups at the heart of the ribosomal decoding machinery can directly affect translational rates, reading frame maintenance, co-translational folding dynamics and overall proteome stability. The variety of tRNA modification patterns is driven by the activity of specialized tRNA modifiers and large modification complexes. Notably, the absence or dysfunction of these cellular machines is correlated with several human pathophysiologies. In this review, we aim to highlight the most recent scientific progress and summarize currently available structural information of the most prominent eukaryotic tRNA modifiers.

The Elongator subunit Elp3 is a non-canonical tRNA acetyltransferase.

The Elongator complex catalyzes posttranscriptional tRNA modifications by attaching carboxy-methyl (cm5) moieties to uridine bases located in the wobble position. The catalytic subunit Elp3 is highly conserved and harbors two individual subdomains, a radical S-adenosyl methionine (rSAM) and a lysine acetyltransferase (KAT) domain. The details of its modification reaction cycle and particularly the substrate specificity of its KAT domain remain elusive. Here, we present the co-crystal structure of bacterial Elp3 (DmcElp3) bound to an acetyl-CoA analog and compare it to the structure of a monomeric archaeal Elp3 from Methanocaldococcus infernus (MinElp3). Furthermore, we identify crucial active site residues, confirm the importance of the extended N-terminus for substrate recognition and uncover the specific induction of acetyl-CoA hydrolysis by different tRNA species. In summary, our results establish the clinically relevant Elongator subunit as a non-canonical acetyltransferase and genuine tRNA modification enzyme.