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Results for “Histidine-tRNA Ligase”

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At least 19 recordsLinked to original sources
PubMed1977

Inhibition of aminoacyl-transfer ribonucleic acid synthetases and the regulation of amino acid biosynthetic enzymes in Neurospora crassa.

Growth conditions that result in the accumulation of the tryptophan intermediate indoleglycerol phosphate or of the histidine intermediate imidazoleglycerol phosphate cause mycelia of Neurospora crassa to exhibit an immediate and sustained increase in the differential rate at which the biosynthetic enzymes of the tryptophan, histidine, and arginine pathways are synthesized. These accumulated intermediates are shown to be inhibitors of the activity of aminoacyltransfer ribonucleic acid (tRNA) synthetases, as judged by an in vitro esterification assay. The tryptophan intermediate is shown to inhibit the charging of tryptophan, and the histidine intermediate is shown to inhibit charging of histidine. The inhibitions noted are consistent with the finding that the level of charged tRNATrp is decreased significantly in cells that have accumulated indoleglycerol phosphate and that of tRNAHis is decreased significantly in cells that have accumulated imidazoleglycerol phosphate. These results are interpreted as support for the involvement of aminoacyl-tRNA species in mediating cross-pathway regulation of the tryptophan, histidine, and arginine biosynthetic pathways as proposed in Lester's polyrepressor hypothesis (G. Lester, 1971). the correlations noted lead to the conclusion that Neurospora utilizes regulatory mechanisms that have the ability to react to changes in the level of charging of tRNA species.

Amino Acyl-tRNA Synthetases↗
PubMed2026

Histidine Supplementation Stabilizes Hearing and Vision and Improves Growth in HARS1-Related Autosomal Recessive Disorder Associated With Usher-Like Symptoms.

Autosomal recessive HARS1-related disorder (originally described as Usher syndrome type 3B) caused by a homozygous Y454S variant in the histidyl-tRNA synthetase gene (HARS1) is characterized by progressive sensorineural hearing and vision loss and respiratory deterioration with risk for sudden death following febrile illnesses. In-vitro studies have previously shown that histidine can rescue a humanized yeast model for pathogenic HARS alleles. Fourteen children homozygous for HARS Y454S were treated with supplemental oral histidine (50 mg/kg BID) and monitored with bloodwork and physical, visual, and audiometry assessments during a 3-year clinical trial, then followed for more than 4 years on histidine in the post-trial period. Patient fibroblasts were assessed for response to histidine. Hearing and vision remained stable, and growth improved significantly. Children remained healthy, with no severe deteriorations despite exposure to bacterial and viral infections, including COVID-19. Gains in growth were maintained in the post-trial period on varying levels of histidine supplementation. Daily oral histidine supplementation in children with autosomal recessive HARS1-related disorder can ameliorate or slow the progression of disease and is safe, inexpensive, and well tolerated. This study adds to the growing list of autosomal recessive ARSopathies (aminoacyl-tRNA synthetase disorders) that are amenable to amino acid supplementation.

Humans↗
PubMed1990

HLA-D region genes associated with autoantibody responses to histidyl-transfer RNA synthetase (Jo-1) and other translation-related factors in myositis.

Myositis has been associated with HLA-B8 and DR3, especially in white patients with polymyositis and serum anti-Jo-1 antibodies. Twenty-eight patients with myositis and serum translation-related autoantibodies anti-Jo-1, anti-PL-7, anti-PL-12, anti-KJ, and anti-SRP were studied for HLA class II specificities by Southern blotting with HLA-DR beta, DQ beta, and DQ alpha probes. The association of HLA-DR3 (DRw17) with anti-Jo-1 antibodies in white myositis patients was confirmed (P = 0.003, relative risk 8.9). However, HLA-DRw52 haplotypes, regardless of subtype, were present in all of the white and black patients with serum anti-Jo-1 and other translation-related autoantibodies. Moreover, one anti-Jo-1 positive patient had HLA-DRw8, an HLA-DRw52 haplotype on which the DR beta 3 gene has been partially deleted. No HLA-DQ specificity or allele was common to all patients. The HLA-DR3, DR5, DRw6, and DRw8 haplotypes, which bear the HLA-DRw52 specificity, share the most homology in the DR beta 1 first hypervariable region at amino acid positions 9-13. Thus, this DR beta 1 region appears to be the most likely candidate "epitope" for translation-related autoimmune responses in inflammatory myositis.

Alleles↗
PubMed1992

Starvation for His-tRNAHis in yeast causes translational arrest without a high level of misincorporation of glutamine at histidine codons.

The hts1.1 temperature-sensitive histidinyl-tRNA synthetase mutation enables Saccharomyces cerevisiae to be starved for His-tRNAHis by upshift to the non-permissive temperature of 38 degrees C. If yeast behaves similarly to bacterial and mammalian cells, this lack of His-tRNAHis should greatly enhance misreading at histidine codons (CAU/CAC) by Gln-tRNAGln, resulting in substitution of the neutral amino acid glutamine in place of histidine, a basic amino acid. Such misreading causes the isoelectric point (pI) of proteins to shift to lower values, and is readily detectable as "stuttering" on two-dimensional (2D) protein gels. By gel analysis of pulse-labelled proteins of hts1.1 yeast cells that were overexpressing phosphoglycerate kinase (PGK), our study sought to detect this specific translational error in PGK protein. It was not detected by this relatively sensitive technique, indicating that missense errors due to glutamine insertion at histidine codons do not occur in yeast at the readily-detectable level found in bacterial and mammalian cells.

Codon↗
PubMed1978

Mutations in the structural genes of CHO cell histidyl-, valyl-, and leucyl-tRNA synthetases.

Forty-three temperature-sensitive mutants were isolated in the CHO cell line by selecting for noncycling cells using [3H]TdR and cytosine arabinoside. Cell division was extremely temperature sensitive in eight of the mutants, and these were studied in more detail. In seven of these eight mutants, the in vitro specific activity of a single aminoacyl-tRNA synthetase was greatly reduced; four had reduced levels of histidyl-tRNA synthetase, two of valyl-tRNA synthetase, and one of leucyl-tRNA synthetase. Cell hybridization studies showed that the mutants formed three complementation groups. In six of the seven mutants the aminoacyl-tRNA synthetase which had reduced activity was also more thermolabile than the wild-type enzyme. The spontaneous reversion frequency was low for these mutants, and in most cases could be increased by treatment with a chemical mutagen. The isolation of the valyl-tRNA synthetase mutant reported here brings to eight the number of different aminoacyl-tRNA synthetase mutants isolated in the CHO cell line.

Amino Acyl-tRNA Synthetases↗
PubMed1992

Sequence and characterization of the gcpE gene of Escherichia coli.

In Escherichia coli, the gene gcpE encodes a protein of unknown function and lies immediately upstream of the hisS gene for histidyl-tRNA synthetase. The nucleic acid sequence of gcpE predicts an open reading frame for a protein of 40,681 Da. The probable transcription terminator of gcpE overlaps the hisS promoter. Haploid cells containing a disrupted gcpE could not be obtained, suggesting that the gcpE gene is essential.

Amino Acid Sequence↗
PubMed1990

The pAX plasmids: new gene-fusion vectors for sequencing, mutagenesis and expression of proteins in Escherichia coli.

A family of plasmid cloning vectors have been constructed, allowing both the sequencing and mutagenesis of foreign genes and the easy isolation of their expression products via fusion proteins in Escherichia coli. Fusion proteins can be inducibly expressed and isolated by affinity chromatography on APTG-Sepharose. The fusion protein consists of beta-galactosidase at the N-terminus, linked by a collagen 'hinge' region containing blood coagulation factor Xa cleavage site to the foreign protein at the C terminus. The factor Xa cleavage site at the N-terminal side of the foreign protein allows the release of the desired amino acid sequence under mild conditions. A multiple cloning site in all three reading frames and stop codons followed by the strong lambda t0 terminator facilitate simple gene insertions and manipulations. The intergenic region of the phage f1 inserted in both orientations allows the isolation of single-stranded DNA from either plasmid-strand for sequencing and mutagenesis. This vector family has been successfully used for the expression and purification of the isoleucyl-tRNA synthetase from Saccharomyces cerevisiae and the histidyl-tRNA synthetase from E. coli.

Base Sequence↗
PubMed1978

Purification and some properties of the histidyl-tRNA synthetase from the cytosol of rabbit reticulocytes.

The histidyl-tRNA synthetase of rabbit reticulocyte cytosol has been purified 84 000-fold to apparent homogeneity with a specific activity of 687 nmol of histidyl-tRNA formed per min per mg of protein. Ten to 15% of the enzyme activity is sedimented with the ribosomes while the remainder is in the cytosol. The purified enzyme has a molecular weight of 122 000 as determined by sucrose density gradient centrifugation. Gel electrophoresis in the presence of 0.1% sodium dodecyl sulfate suggests that it is composed of two similar subunits with a molecular weight of approximately 64 000. The enzyme has a magnesium optimum of 45 mM; however, this is reduced to 5 mM in the presence of an intracellular potassium concentration (160 nM). The enzyme acylates the two histidine tRNA isoacceptors of rabbit reticulocytes with similar Km values and at similar rates.

Amino Acyl-tRNA Synthetases↗
PubMed1990

The role of an autoantigen, histidyl-tRNA synthetase, in the induction and maintenance of autoimmunity.

Patients with systemic autoimmune diseases make specific autoantibodies that are directed against self structures. According to one view, these autoantibodies arise as a result of an immune response to foreign antigens such as infectious agents that share, by molecular mimicry, common structures with host proteins. An alternative view is that the target autoantigen itself initiates, selects, and sustains autoantibody synthesis. We show here that anti-Jo-1 autoantibodies directed against histidyl-tRNA synthetase in the human autoimmune muscle disease polymyositis undergo, in addition to spectrotype broadening and class switching, the sine qua non of an immune response to the target antigen--affinity maturation to that antigen. We demonstrate further that these autoantibodies, unlike anti-synthetase antibodies induced in mice immunized with heterologous antigen, bind only nonlinear epitopes on the native human synthetase that remain exposed when the enzyme is complexed to tRNA(His). These data suggest that the native target autoantigen itself has played a direct role in selecting and sustaining the autoantibody response and sharply restrict the time and the way in which a molecular mimic might act to provoke autoantibodies.

Animals↗
PubMed1992

HTS1 encodes both the cytoplasmic and mitochondrial histidyl-tRNA synthetase of Saccharomyces cerevisiae: mutations alter the specificity of compartmentation.

Genetic and biochemical evidence shows that a single nuclear gene HTS1 encodes both the mitochondrial and cytoplasmic histidyl-tRNA synthetases (Hts). The gene specifies two messages, one with two in-frame ATGs (-60 and +1) and another with only the downstream ATG (+1). We have made a new set of mutations that enables us to express only the mitochondrial or the cytoplasmic form and compared the subcellular distribution of the Hts1 protein in these mutants and wild type, using an antibody that interacts with both the mitochondrial and cytoplasmic Hts1 as well as Hts1::LacZ fusions. Mutations in the upstream ATG (-60) or frameshift mutations in the presequence affect only the mitochondrial enzyme and not the cytoplasmic enzyme. Mutations in the downstream ATG (+1 ATG to ATC) destroy the function of the cytosolic enzyme, but do not affect the function of the mitochondrial enzyme. Overexpression of this construct restores cytoplasmic function. Cells expressing a truncated form of Hts containing a deletion of the first 20 amino-terminal residues (Htsc) produce a functional cytoplasmic enzyme, which does not provide mitochondrial function. Overexpression of this truncated cytoplasmic protein provides mitochondrial function and produces detectable levels of the synthetase in the mitochondrion. These experiments suggest that Hts1 contains two domains that together allow efficient localization of Htsm to the mitochondrion: an amino-terminal presequence in the mitochondrial precursor that is likely cleaved upon delivery to the mitochondrion and a second amino-terminal sequence (residues 21-53) present in both the precursor and the cytoplasmic form. Neither one by itself is sufficient to act as an efficient mitochondrial targeting signal. Using our antibody we have been able to detect a protein of increased molecular mass that corresponds to that of the predicted precursor. Taken together these studies show that the specificity of compartmentation of the Hts protein depends upon both the primary sequence and the concentration of the protein in the cell.

Base Sequence↗
PubMed1992

Human histidyl-tRNA synthetase: recognition of amino acid signature regions in class 2a aminoacyl-tRNA synthetases.

We have determined the sequence of cDNA for the human histidyl-tRNA synthetase (HRS) in a hepatoma cell line and confirmed it in fetal myoblast and fibroblast cell lines. The newly determined sequence differs in 48 places, including insertions and deletions, from a previously published sequence. By sequence specific probing and by direct sequencing, we have established that only the newly determined sequence is present in genomic DNA and we have sequenced 500 hundred bases upstream of the translation start site. The predicted amino acid sequence now clearly demonstrates all three motifs recognized in class 2 aminoacyl-tRNA synthetases. Alignment of E. coli, yeast, and when available, mammalian predicted amino acid sequences for three of the four members of the class 2a subgroup (his, pro, ser, and thr) shows strong preservation of amino acid specific signature regions proximal to motif 2 and proximal to motif 3. These probably represent the active site binding regions for the proximal acceptor stem and for the amino acid. The first two exons of human HRS contain a 32 amino acid helical motif, first described in human QRS, a class 1 synthetase, which is found also in a yeast RNA polymerase, a rabbit termination factor, and both bovine and human WRS, suggesting that it may be an RNA binding motif.

Amino Acid Sequence↗
PubMed1992

Efficient mischarging of a viral tRNA-like structure and aminoacylation of a minihelix containing a pseudoknot: histidinylation of turnip yellow mosaic virus RNA.

Mischarging of the valine specific tRNA-like structure of turnip yellow mosaic virus (TYMV) RNA has been tested in the presence of purified arginyl-, aspartyl-, histidinyl-, and phenylalanyl-tRNA synthetases from bakers' yeast. Important mischarging of a 264 nucleotide-long transcript was found with histidinyl-tRNA synthetase which can acylate this fragment up to a level of 25% with a loss of specificity (expressed as Vmax/KM ratios) of only 100 fold as compared to a yeast tRNA(His) transcript. Experiments on transcripts of various lengths indicate that the minimal valylatable fragment (n = 88) is the most efficient substrate for histidinyl-tRNA synthetase, with kinetic characteristics similar to those found for the control tRNA(His) transcript. Mutations in the anticodon or adjacent to the 3' CCA that severely affect the valylation capacity of the 264 nucleotide long TYMV fragment are without negative effect on its mischarging, and for some cases even improve its efficiency. A short fragment (n = 42) of the viral RNA containing the pseudoknot and corresponding to the amino acid accepting branch of the molecule is an efficient histidine acceptor.

Base Sequence↗
PubMed1990

Lymphocyte activation markers in idiopathic myositis: changes with disease activity and differences among clinical and autoantibody subgroups.

We studied the immunologic correlates of disease activity and differences among subgroups of patients with idiopathic inflammatory myopathy by analysing phenotypic and activation marker expression on peripheral blood mononuclear cells (PBMC). Compared with controls, myositis patients with clinically active disease (n = 51) had significantly lower proportions of CD8+ cells and higher proportions of PBMC that expressed DR, CD3- DR, CD14- DR, interleukin-2 receptors, and the late T cell activation markers CD26 and TLiSA1. TLiSA1 expression, a marker for cytotoxic differentiation, correlated significantly with both clinical activity indices and serum levels of muscle-associated enzymes. In serial studies of seven patients, the proportion of PBMC expressing MHC class II antigen and late T cell activation markers decreased as myositis disease activity decreased, independent of type of therapy. Among the clinical subgroups, polymyositis (n = 21) and inclusion body myositis (n = 11) were virtually indistinguishable; dermatomyositis patients (n = 19) showed decreased proportions of CD3+DR+ and TLiSA1+ cells, and increased proportions of CD20+ and CD20+DR+ cells compared with the other two groups. Patients with autoantibodies to histidyl-tRNA synthetase (Jo-1 antigen, n = 11) had significantly lower proportions of CD3+ and CD4+ cells, lower CD4/CD8 ratios, and higher proportions of CD+ cells expressing CD20, compared with patients without anti-Jo-1 antibodies. These findings support the concept that activated lymphocytes, especially cells undergoing anamnestic responses and cytotoxic differentiation, are important in the pathogenesis of idiopathic myositis. Moreover, taken together with other studies, these data suggest that groups of patients segregated by clinical or autoantibody status have different mechanisms of systemic immune activation and immunopathology.

Adult↗