Abstract
D-aminoacyl-tRNA deacylase (DTD), a bacterial/eukaryotic trans-editing factor, removes d-amino acids mischarged on tRNAs and achiral glycine mischarged on tRNAAla. An invariant cross-subunit Gly-cisPro motif forms the mechanistic basis of l-amino acid rejection from the catalytic site. Here, we present the identification of a DTD variant, named ATD (Animalia-specific tRNA deacylase), that harbors a Gly-transPro motif. The cis-to-trans switch causes a “gain of function” through L-chiral selectivity in ATD resulting in the clearing of l-alanine mischarged on tRNAThr(G4•U69) by eukaryotic AlaRS. The proofreading activity of ATD is conserved across diverse classes of phylum Chordata. Animalia genomes enriched in tRNAThr(G4•U69) genes are in strict association with the presence of ATD, underlining the mandatory requirement of a dedicated factor to proofread tRNA misaminoacylation. The study highlights the emergence of ATD during genome expansion as a key event associated with the evolution of Animalia.
Highlights
D-aminoacyl-tRNA deacylase (DTD), a bacterial/eukaryotic trans-editing factor, removes D-amino acids mischarged on tRNAs and achiral glycine mischarged on tRNAAla
The most notable among these is a highly conserved arginine in DTD (Arg[7] in DTD from Escherichia coli (EcDTD) or Plasmodium falciparum (PfDTD)), which is replaced by a conserved glutamine in Animalia-specific tRNA deacylase (ATD) (Gln[16] in ATD from Mus musculus (MmATD)) (Fig. 1a)
Our extensive structural and biochemical probing in combination with in-depth in silico analysis confirms that ATD serves as a dedicated factor for correcting the tRNAThr(G4U69) selection error committed by eukaryotic AlaRS can be called non-discriminating AlaRS (AlaRSND) (Fig. 8)
Summary
D-aminoacyl-tRNA deacylase (DTD), a bacterial/eukaryotic trans-editing factor, removes D-amino acids mischarged on tRNAs and achiral glycine mischarged on tRNAAla. An invariant cross-subunit Gly-cisPro motif forms the mechanistic basis of L-amino acid rejection from the catalytic site. Translational quality control is a complex and tightly regulated process which involves editing of errors in most scenarios It encompasses a targeted and selective compromise in fidelity, thereby allowing percolation of errors under specific conditions such as oxidative stress. In archaea, which lack DTD, a DTD-like module is covalently appended to threonyl-tRNA synthetase (ThrRS) as the N-terminal domain (NTD) that edits Lserine misacylated on tRNAThr[23,24,25,26] Both DTD-like fold (comprising DTD and NTD) and chiral proofreading function (performed by DTD, DTD2, and DTD3) are conserved across all domains of life. Errors in amino acid selection by synthetases are a β1
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