Specificity and catalysis hardwired at the RNA-protein interface in a translational proofreading enzyme

Nat Commun. 2015 Jun 26;6:7552. doi: 10.1038/ncomms8552.


Proofreading modules of aminoacyl-tRNA synthetases are responsible for enforcing a high fidelity during translation of the genetic code. They use strategically positioned side chains for specifically targeting incorrect aminoacyl-tRNAs. Here, we show that a unique proofreading module possessing a D-aminoacyl-tRNA deacylase fold does not use side chains for imparting specificity or for catalysis, the two hallmark activities of enzymes. We show, using three distinct archaea, that a side-chain-stripped recognition site is fully capable of solving a subtle discrimination problem. While biochemical probing establishes that RNA plays the catalytic role, mechanistic insights from multiple high-resolution snapshots reveal that differential remodelling of the catalytic core at the RNA-peptide interface provides the determinants for correct proofreading activity. The functional crosstalk between RNA and protein elucidated here suggests how primordial enzyme functions could have emerged on RNA-peptide scaffolds before recruitment of specific side chains.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acyl-tRNA Synthetases / genetics
  • Amino Acyl-tRNA Synthetases / metabolism*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Catalytic Domain
  • Cloning, Molecular
  • Gene Expression Regulation, Bacterial / physiology*
  • Gene Expression Regulation, Enzymologic
  • Models, Molecular
  • Protein Conformation
  • Protein Processing, Post-Translational
  • RNA / metabolism*
  • RNA Editing / physiology*


  • Bacterial Proteins
  • RNA
  • Amino Acyl-tRNA Synthetases