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

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Abstract

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.

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Abbreviations

AaRS:

Aminoacyl-tRNA synthetase

cDNA:

Complementary DNA

DAPI:

4′,6-Diamidino-2-phenylindole

5-FOA:

5-Fluoroorotic acid

GFP:

Green fluorescence protein

HisRS:

Histidyl-tRNA synthetase

MTS:

Mitochondrial targeting signal

ORF:

Open-reading frame

PCR:

Polymerase chain reaction

PGK:

Phosphoglycerate kinase

Thg1:

tRNAHis guanylyltransferase

WT:

Wild-type

YPG:

Yeast extract peptone glycerol.

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Acknowledgements

This work was supported by Grants MOST 103-2311-B-008-003-MY3, MOST 103-2923-B-008-001-MY3, and NSC 102-2311-B-008-004-MY3 (to C.C.W.) from the Ministry of Science and Technology (Taipei, Taiwan).

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Authors and Affiliations

  1. Department of Life Sciences, National Central University, Jungli District, Taoyuan, 32001, Taiwan

    Yi-Hsueh Lee, Chia-Pei Chang, Yu-Ju Cheng, Yi-Yi Kuo & Chien-Chia Wang

  2. Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, 30068, Taiwan

    Yeong-Shin Lin

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Correspondence to Chien-Chia Wang.

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Lee, YH., Chang, CP., Cheng, YJ. et al. Evolutionary gain of highly divergent tRNA specificities by two isoforms of human histidyl-tRNA synthetase. Cell. Mol. Life Sci. 74, 2663–2677 (2017). https://doi.org/10.1007/s00018-017-2491-3

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