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Gene Review

HARS2  -  histidyl-tRNA synthetase 2, mitochondrial

Homo sapiens

Synonyms: HARSL, HARSR, HO3, HisRS, Histidine--tRNA ligase-like, ...
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Disease relevance of HARS2

  • Residues corresponding to amino acids at the dimer interface of Escherichia coli HisRS were required for dimerization of recombinant HisRS-N and for tRNA binding by full-length GCN2, suggesting that HisRS-N dimerization promotes tRNA binding and kinase activation [1].
  • Human immunodeficiency virus type 1 matrix protein interacts with cellular protein HO3 [2].
  • Correspondingly, overexpression of HO3 in virus producer cells enhanced the infectivity of wild-type but not MA(KK27AA) HIV-1 particles [2].
  • When overexpressed in HIV-1-producing cells, HO3 was incorporated into wild-type virions but not in ones containing the dilysine-mutated variant of MA [2].
  • HisRS homologs that, like HisZ, cannot aminoacylate tRNA are represented in a highly divergent set of bacteria (including an aquificale, cyanobacteria, firmicutes, and proteobacteria), yet are missing from other bacteria, including mycrobacteria and certain proteobacteria [3].

High impact information on HARS2

  • These results identify an inhibitory structure intrinsic to the PK domain that must be overcome on tRNA binding by interactions with a regulatory region, most likely the N terminus of the HisRS segment [4].
  • An NH(2)-terminal domain, 1-48 HisRS, was chemotactic for lymphocytes and activated monocytes, whereas a deletion mutant, HisRS-M, was inactive [5].
  • Furthermore, monoclonal anti-CCR5 blocked HisRS-induced chemotaxis and conversely, HisRS blocked anti-CCR5 binding [5].
  • Additionally, mutational analysis identifies the histidine binding sites within a region highly conserved between HisZ and the functional HisRS [6].
  • Since the KIE for the hypothetical H-atom transfer: O3 + HO2- HO3. +.O2-, would emerge as a KIE1/2 factor in the rates of the ensuing radical chain, the magnitude of the observed KIE must be associated with the hydride transfer reaction that yields a diamagnetic species: O3 + HO2- HO3- + O2 [7].

Biological context of HARS2


Anatomical context of HARS2

  • HO3-specific mRNA was detected in several tissues relevant for HIV infection, such as spleen, thymus, and peripheral blood lymphocytes, as well as in a number of T-lymphoid-cell lines [2].
  • Occasional fluorescent spots seen in the nuclear region coincided with the immunofluorescent stain of the nuclear pore complex, indicating that they represent GFP-tagged HisRS in the cytoplasm that had invaginated deeply into the nucleus [10].

Associations of HARS2 with chemical compounds

  • The crystal structures of HisRS from two organisms and their complexes with histidine, histidyl-adenylate and histidinol with ATP have been solved [11].
  • HisRS also belongs to the group of aaRS that can rapidly synthesize diadenosine tetraphosphate, a compound that is suspected to be involved in several regulatory mechanisms of cell metabolism [11].
  • Aminoacyl transfer experiments using HisRS active site mutants and phosphorothioate-substituted adenylate showed that substitution of the nonbridging Sp oxygen of the adenylate decreased the transfer rate at least 10 000-fold, providing direct experimental evidence for the role of this group as a general base for the reaction [12].
  • Infrared detection of HO2 and HO3 radicals in water ice [13].

Other interactions of HARS2

  • In this report, we describe the genomic organization of the HARS/HARSL locus and map multiple transcripts originating from a bi-directional promoter controlling the differential expression of these genes [8].

Analytical, diagnostic and therapeutic context of HARS2

  • We have isolated and characterized a human genomic DNA clone that encodes portions of these oppositely transcribed mRNAs and a putatively full-length cDNA clone (HO3) corresponding to the gene mapping immediately 5' of HRS [9].


  1. The tRNA-binding moiety in GCN2 contains a dimerization domain that interacts with the kinase domain and is required for tRNA binding and kinase activation. Qiu, H., Dong, J., Hu, C., Francklyn, C.S., Hinnebusch, A.G. EMBO J. (2001) [Pubmed]
  2. Human immunodeficiency virus type 1 matrix protein interacts with cellular protein HO3. Lama, J., Trono, D. J. Virol. (1998) [Pubmed]
  3. Proteobacterial histidine-biosynthetic pathways are paraphyletic. Bond, J.P., Francklyn, C. J. Mol. Evol. (2000) [Pubmed]
  4. Mutations that bypass tRNA binding activate the intrinsically defective kinase domain in GCN2. Qiu, H., Hu, C., Dong, J., Hinnebusch, A.G. Genes Dev. (2002) [Pubmed]
  5. Histidyl-tRNA synthetase and asparaginyl-tRNA synthetase, autoantigens in myositis, activate chemokine receptors on T lymphocytes and immature dendritic cells. Howard, O.M., Dong, H.F., Yang, D., Raben, N., Nagaraju, K., Rosen, A., Casciola-Rosen, L., Härtlein, M., Kron, M., Yang, D., Yiadom, K., Dwivedi, S., Plotz, P.H., Oppenheim, J.J. J. Exp. Med. (2002) [Pubmed]
  6. Activation of the hetero-octameric ATP phosphoribosyl transferase through subunit interface rearrangement by a tRNA synthetase paralog. Champagne, K.S., Sissler, M., Larrabee, Y., Doublié, S., Francklyn, C.S. J. Biol. Chem. (2005) [Pubmed]
  7. Hydrogen isotope effects and mechanism of aqueous ozone and peroxone decompositions. Lesko, T.M., Colussi, A.J., Hoffmann, M.R. J. Am. Chem. Soc. (2004) [Pubmed]
  8. Genomic organization, transcriptional mapping, and evolutionary implications of the human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL). O'Hanlon, T.P., Miller, F.W. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  9. A novel gene oriented in a head-to-head configuration with the human histidyl-tRNA synthetase (HRS) gene encodes an mRNA that predicts a polypeptide homologous to HRS. O'Hanlon, T.P., Raben, N., Miller, F.W. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  10. Intracellular localization of histidyl-tRNA synthetase/Jo-1 antigen in T24 cells and some other cells. Kamei, H. J. Autoimmun. (2004) [Pubmed]
  11. Histidyl-tRNA synthetase. Freist, W., Verhey, J.F., Rühlmann, A., Gauss, D.H., Arnez, J.G. Biol. Chem. (1999) [Pubmed]
  12. A substrate-assisted concerted mechanism for aminoacylation by a class II aminoacyl-tRNA synthetase. Guth, E., Connolly, S.H., Bovee, M., Francklyn, C.S. Biochemistry (2005) [Pubmed]
  13. Infrared detection of HO2 and HO3 radicals in water ice. Cooper, P.D., Moore, M.H., Hudson, R.L. The journal of physical chemistry. A, Molecules, spectroscopy, kinetics, environment & general theory. (2006) [Pubmed]
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