Internally deleted human tRNA synthetase suggests evolutionary pressure for repurposing

Structure. 2012 Sep 5;20(9):1470-7. doi: 10.1016/j.str.2012.08.001.


Aminoacyl-tRNA synthetases (AARSs) catalyze aminoacylation of tRNAs in the cytoplasm. Surprisingly, AARSs also have critical extracellular and nuclear functions. Evolutionary pressure for new functions might be manifested by splice variants that skip only an internal catalytic domain (CD) and link noncatalytic N- and C-terminal polypeptides. Using disease-associated histidyl-tRNA synthetase (HisRS) as an example, we found an expressed 171-amino acid protein (HisRSΔCD) that deleted the entire CD, and joined an N-terminal WHEP to the C-terminal anticodon-binding domain (ABD). X-ray crystallography and three-dimensional NMR revealed the structures of human HisRS and HisRSΔCD. In contrast to homodimeric HisRS, HisRSΔCD is monomeric, where rupture of the ABD's packing with CD resulted in a dumbbell-like structure of flexibly linked WHEP and ABD domains. In addition, the ABD of HisRSΔCD presents a distinct local conformation. This natural internally deleted HisRS suggests evolutionary pressure to reshape AARS tertiary and quaternary structures for repurposing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / blood
  • Antibodies / immunology
  • Base Sequence
  • Catalytic Domain
  • Crystallography, X-Ray
  • DNA, Complementary / genetics
  • Evolution, Molecular*
  • High-Throughput Nucleotide Sequencing
  • Histidine-tRNA Ligase / chemistry*
  • Histidine-tRNA Ligase / genetics
  • Histidine-tRNA Ligase / immunology
  • Humans
  • Lung Diseases, Interstitial / blood
  • Lung Diseases, Interstitial / immunology
  • Models, Molecular
  • Molecular Sequence Data
  • Myositis / blood
  • Myositis / immunology
  • Protein Isoforms
  • Protein Structure, Secondary
  • Sequence Analysis, DNA
  • Sequence Deletion*
  • Transcriptome


  • Antibodies
  • DNA, Complementary
  • Protein Isoforms
  • Histidine-tRNA Ligase

Associated data

  • PDB/4G84
  • PDB/4G85