Tyrosine–tRNA ligase (EC 6.1.1.1), also known as tyrosyl-tRNA synthetase, is an enzyme that is encoded by the gene YARS. Tyrosine–tRNA ligase catalyzes the chemical reaction
ATP + L-tyrosine + tRNATyr ⇌ {\displaystyle \rightleftharpoons } AMP + diphosphate + L-tyrosyl-tRNATyr The three substrates of this enzyme are ATP, L-tyrosine, and a tyrosine-specific transfer RNA tRNATyr, whereas its three products are AMP, diphosphate, and L-tyrosyl-tRNATyr. This enzyme belongs to the family of ligases, to be specific those forming carbon-oxygen bonds in tRNA and related compounds. More specifically, it belongs to the family of the aminoacyl-tRNA synthetases. These latter enzymes link amino acids to their cognate transfer RNAs (tRNA) in aminoacylation reactions that establish the connection between a specific amino acid and a nucleotide triplet anticodon embedded in the tRNA. Therefore, they are the enzymes that translate the genetic code in vivo. The 20 enzymes, corresponding to the 20 natural amino acids, are divided into two classes of 10 enzymes each. This division is defined by the unique architectures associated with the catalytic domains and by signature sequences specific to each class.
Structural studies As of late 2007, 34 structures have been solved for this class of enzymes, with PDB accession codes The tyrosyl-tRNA synthetases (YARS) are either homodimers or monomers with a pseudo-dimeric structure. Each subunit or pseudo-subunit comprises an N-terminal domain which has: (i) about 230 amino acid residues; (ii) the mononucleotide binding fold (also known as Rossmann fold) of the class I aminoacyl-tRNA synthetases; (iii) an idiosynchratic insertion between the two halves of the fold (known as Connective Peptide 1 or CP1); (iv) the two signature sequences HIGH and KMSKS of the class I aminoacyl-tRNA synthetases. The N-terminal domain contains the catalytic site of the enzyme. The C-terminal moiety of the YARSs varies in sequence, length and organization and is involved in the recognition of the tRNA anticodon.
Eubacteria Tyrosyl-tRNA synthetase from Bacillus stearothermophilus was the first synthetase whose crystal structure has been solved at high resolution (2.3 Å), alone or in complex with tyrosine, tyrosyl-adenylate or tyrosinyl-adenylate.(P. Brick 1989) The structures of the Staphylococcus aureus YARS and of a truncated version of Escherichia coli YARS have also been solved. A structural model of the complex between B. sterothermophilus YARS and tRNATyr was constructed using extensive mutagenesis data on both YARS and tRNATyr and found consistent with the crystal structure of the complex between YARS and tRNATyr from Thermus thermophilus, which was subsequently solved at 2.9 Å resolution. The C-terminal moiety of the eubacterial YARSs comprises two domains: (i) a proximal α-helical domain (known as Anticodon Binding Domain or α-ACB) of about 100 amino acids; (ii) a distal domain (known as S4-like) that shares high homology with the C-terminal domain of ribosomal protein S4. The S4-like domain was disordered in the crystal structure of B. stearothermophilus YARS. However, biochemical and NMR experiments have shown that the S4-like domain is folded in solution, and that its structure is similar to that in the crystal structure of the T. thermophilus YARS. Mutagenesis experiments have shown that the flexibility of the peptide that links the α-ACB and S4-like domains is responsible for the disorder of the latter in the structure and that elements of sequence in this linker peptide are essential for the binding of tRNATyr by YARS and its aminoacylation with tyrosine. TyrRSs from eubacterial species are divided into two subgroups according to variation in their C-terminal moiety.
Archaea and lower eukaryotes The crystal structures of several archaeal tyrosyl-tRNA synthetases are available. The crystal structure of the complex between YARS from Methanococcus jannaschii, tRNATyr and L-tyrosine has been solved at 1.95 Å resolution. The crystal structures of the YARSs from Archeoglobus fulgidus, Pyrococcus horikoshii and Aeropyrum pernix have also been solved at high resolution.(M. Kuratani 2006) The C-terminal moieties of the archaeal YARSs contain only one domain. This domain is different from the α-ACB domain of eubacteria; it shares strong homology with the C-terminal domain of the tryptophanyl-tRNA synthetases and was therefore named C-W/Y domain. It is present in all eukarya. The structure of the complex between YARS from Saccharomyces cerevisiae, tRNATyr and an analog of tysosyl-adenylate has been solved at 2.4 Å resolution. The YARS from this lower eukaryote has an organization which is similar to that of the archaeal YARSs.
Homo sapiens cytoplasm The human YARS has a C-terminal moiety that include a proximal C-W/Y domain and a distal domain which is not found in the YARSs of lower eukaryotes, archaea or eubacteria, and is a homolog of endothelial monocyte-activating polypeptide II (EMAP II, a mammalian cytokine). Although full-length, native YARS has no cell-signaling activity, the enzyme is secreted during apoptosis in cell culture and can be cleaved with an extracellular enzyme such as leukocyte elastase. The two released fragments, an N-terminal mini-YARS and a C-terminal EMAP II-like C-terminal domain, are active cytokines. The structure of mini-YARS has been solved at 1.18 Å resolution. It has an N-terminal Rossmann-fold domain and a C-terminal C-W/Y domain, similar to those of other YARSs.
Homo sapiens mitochondria The mitochondrial tyrosyl-tRNA synthetases (mt-YARSs) and in particular H. sapiens mt-YARS, likely originate from a YARS of eubacterial origin. Their C-terminal moiety includes both α-ACB and S4-like domains like the eubacterial YARSs and share a low sequence identity with their cytosolic relatives. The crystal structure of a complex between a recombinant H. sapiens mt-YARS, devoid of the S4-like domain, and an analog of tyrosyl-adenylate has been solved at 2.2 Å resolution.
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