Histidyl-tRNA Synthetase

Abstract

Histidyl-tRNA synthetase (HisRS) is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. This amino acid has uniquely moderate basic properties and is an important group in many catalytic functions of enzymes.A compilation of currently known primary structures of HisRS shows that the subunits of these homodimeric enzymes consist of 420 -550 amino acid residues. This represents a relatively short chain length among aminoacyl-tRNA synthetases (aaRS), whose peptide chain sizes range from about 300 to 1100 amino acid residues.The crystal structures of HisRS from two organisms and their complexes with histidine, histidyl-adenylate and histidinol with ATP have been solved. HisRS from Escherichia coli and Thermus thermophilus are very similar dimeric enzymes consisting of three domains: the N-terminal catalytic domain containing the sixstranded antiparallel ␤-sheet and the three motifs characteristic of class II aaRS, a HisRS-specific helical domain inserted between motifs 2 and 3 that may contact the acceptor stem of the tRNA, and a C-terminal ␣/␤ domain that may be involved in the recognition of the anticodon stem and loop of tRNA His .The aminoacylation reaction follows the standard two-step mechanism. 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. Many analogs of histidine have been tested for their properties as substrates or inhibitors of HisRS, leading to the elucidation of structure-activity relationships concerning configuration, importance of the carboxy and amino group, and the nature of the side chain.HisRS has been found to act as a particularly important antigen in autoimmune diseases such as rheumatic arthritis or myositis. Successful attempts have been made to identify epitopes responsible for the complexation with such auto-antibodies.

Human Cytomegalovirus UL84 Interacts with an RNA Stem-Loop Sequence Found within the RNA/DNA Hybrid Region of ori Lyt

“…While it is possible that UL84 does contain a six-stranded beta-barrel structural component at the C terminus, until a crystal structure of the protein is analyzed, this analysis cannot be confirmed. Furthermore this structural fold is found in many classes of enzymes and by no means strictly defines the protein as a dUTPase (14,28). Our initial structural inquiries indicate that the beta-barrel fold in UL84 more closely resembles that in a tRNA synthetase-like enzyme and may represent an RNA stem-loop binding site (unpublished data).…”

Plant tumour biocontrol agent employs a tRNA-dependent mechanism to inhibit leucyl-tRNA synthetase

“…To circumvent this, we explored the requirement for tRNA Leu in the inhibition mechanism of TM84 by adding in vitro transcribed tRNA Leu to the ATP/PPi-exchange reaction. This approach has been used before for aaRS enzymes such as glutaminyl- 26 and glutamyl-tRNA synthetases 27 , which, unlike LeuRSs, require tRNA for the activation reaction to proceed. Importantly, in these experiments we used an active tRNA Leu concentration of 6.7 mM that had no effect on the initial rate of ATP/PPi exchange for the LeuRS At reaction (Fig.…”

Genomic organization, transcriptional mapping, and evolutionary implications of the human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL)

“…Histidyl-tRNA synthetase (HARS), the enzyme that synthesizes His-tRNA, is one member of the aaRS gene family that has been well characterized in a variety of species including humans, owing in part to its targeting by autoantibodies in patients with the autoimmune muscle diseases polymyositis and dermatomyositis [4][5][6]. In humans and rodents, the HisRS open reading frame (ORF) is preceded by a bi-directional promoter that coordinates the transcription of multiple mRNAs in opposite directions [7,8].…”