Evolutionary gain of highly divergent tRNA specificities by two isoforms of human histidyl-tRNA synthetase

Yi Hsueh Lee, Chia Pei Chang, Yu Ju Cheng, Yi Yi Kuo, Yeong-Shin Lin, Chien Chia Wang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


The discriminator base N73 is a key identity element of tRNAHis. In eukaryotes, N73 is an “A” in cytoplasmic tRNAHis and a “C” in mitochondrial tRNAHis. We present evidence herein that yeast histidyl-tRNA synthetase (HisRS) recognizes both A73 and C73, but somewhat prefers A73 even within the context of mitochondrial tRNAHis. In contrast, humans possess two distinct yet closely related HisRS homologues, with one encoding the cytoplasmic form (with an extra N-terminal WHEP domain) and the other encoding its mitochondrial counterpart (with an extra N-terminal mitochondrial targeting signal). Despite these two isoforms sharing high sequence similarities (81% identity), they strongly preferred different discriminator bases (A73 or C73). Moreover, only the mitochondrial form recognized the anticodon as a strong identity element. Most intriguingly, swapping the discriminator base between the cytoplasmic and mitochondrial tRNAHis isoacceptors conveniently switched their enzyme preferences. Similarly, swapping seven residues in the active site between the two isoforms readily switched their N73 preferences. This study suggests that the human HisRS genes, while descending from a common ancestor with dual function for both types of tRNAHis, have acquired highly specialized tRNA recognition properties through evolution.

Original languageAmerican English
Pages (from-to)2663-2677
Number of pages15
JournalCellular and Molecular Life Sciences
Issue number14
StatePublished - 1 Jul 2017


  • Aminoacyl-tRNA synthetase
  • Evolution
  • Phylogenetic analysis
  • Protein synthesis
  • Subfunctionalization
  • tRNA


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