Recognition of †RNAs by Aminoacyl-†RNA Synthetases
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Amino Acyl-tRNA Synthetases
Amino Acyl-tRNA Synthetases
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Codon-dependent translation underlies genetics and phylogenetic inferences, but its origins pose two challenges. Prevailing narratives cannot account for the fact that aminoacyl-tRNA synthetases (aaRSs), which translate the genetic code, must collectively enforce the rules used to assemble themselves. Nor can they explain how specific assignments arose from rudimentary differentiation between ancestral aaRSs and corresponding transfer RNAs (tRNAs). Experimental deconstruction of the two aaRS superfamilies created new experimental tools with which to analyze the emergence of the code. Amino acid and tRNA substrate recognition are linked to phase transfer free energies of amino acids and arise largely from aaRS class-specific differences in secondary structure. Sensitivity to protein folding rules endowed ancestral aaRS-tRNA pairs with the feedback necessary to rapidly compare alternative genetic codes and coding sequences. These and other experimental data suggest that the aaRS bidirectional genetic ancestry stabilized the differentiation and interdependence required to initiate and elaborate the genetic coding table.
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Abstract Aminoacyl‐tRNA synthetases catalyse a key reaction in protein biosynthesis. They match the 20 amino acids to the genetic code by specifically attaching them to their adaptors, transfer ribonucleic acid (tRNA) molecules.
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Genetic code expansion (GCE) enables the site-specific incorporation of unnatural amino acids (uAAs) into proteins in living cells. This is typically achieved by using an engineered orthogonal aminoacyl-tRNA synthetase (aaRS)/tRNA pair that directs the incorporation of the uAA according to an amber codon introduced into a gene of interest. Within this thesis I have developed and optimized GCE-tools (including novel uAAs and aaRS/tRNA pairs) to study and validate protein-protein interactions.
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In the past two decades, tRNA molecules and their corresponding aminoacyl-tRNA synthetases (aaRS) have been extensively used in synthetic biology to genetically encode post-translationally modified and unnatural amino acids. In this review, we briefly examine one fundamental requirement for the successful application of tRNA/aaRS pairs for expanding the genetic code. This requirement is known as "orthogonality"-the ability of a tRNA and its corresponding aaRS to interact exclusively with each other and avoid cross-reactions with additional types of tRNAs and aaRSs in a given organism.
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The ability to incorporate unnatural amino acids into proteins directly in living cells will provide new tools to study protein and cellular function, and may generate proteins or even organisms with enhanced properties. Due to the limited promiscuity of some synthetases, natural amino acids can be substituted with close analogs at multiple sites using auxotrophic strains. Alternatively, this can be achieved by deactivating the editing function of some synthetases. The addition of new amino acids to the genetic code, however, requires additional components of the protein biosynthetic machinery including a novel tRNA-codon pair, an aminoacyl-tRNA synthetase, and an amino acid. This new set of components functions orthogonally to the counterparts of the common 20 amino acids, i.e., the orthogonal synthetase (and only this synthetase) aminoacylates the orthogonal tRNA (and only this tRNA) with the unnatural amino acid only, and the resulting acylated tRNA inserts the unnatural amino acid only in response to the unique codon. Using this strategy, the genetic code of Escherichia coli has been expanded to incorporate unnatural amino acids with a fidelity rivaling that of natural amino acids. This methodology is being applied to other cell types and unnatural analogs with a variety of functionalities.
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Amino Acyl-tRNA Synthetases
Amino Acyl-tRNA Synthetases
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Proteins of the primitive cells probably contained only a few of the 20 amino acid species presently incorporated into proteins. The 20 corresponding species of aminoacyl-tRNA synthetases found in most cells could result from the divergent evolution of the genes of one or a few primitive aminoacyl-tRNA synthetases. A comparison of the structural and catalytic properties of the 20 aminoacyl-tRNA synthetases should help to determine the steps of this evolution, which is also that of the genetic code. First, the very diverse quaternary structures of these synthetases are not generally correlated with the evolutionary linkages suggested by many theories of the evolution of the genetic code. The results discussed here indicate that these quaternary structures are more related to the various regulatory functions of the aminoacyl-tRNA synthetases than to their basic function which is the specific aminoacylation of tRNAs. Secondly, a comparison of the catalytic peculiarities of these enzymes appears to be useful for understanding the evolution of the genetic code; for instance, the requirement for the presence of tRNA in the activation of glutamate, glutamine, and arginine by the corresponding aminoacyl-tRNA synthetases, and the absence, in some Gram-positive bacteria, of a glutaminyl-tRNA synthetase, which is replaced by a less specific glutamyl-tRNA synthetase and an amido-transferase of Glu-tRNA Gln , suggest that these three aminoacyl-tRNA synthetases specific for amino acids of the glutamate family have a common ancestor. Finally, the comparison of the sequences of the structural genes of these enzymes is a promising approach for studying their evolution and that of the genetic code.
Amino Acyl-tRNA Synthetases
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Aminoacyl-tRNA synthetases (AARS) are essential proteins found in all living organisms. They form a diverse group of enzymes that ensure the fidelity of transfer of genetic information from the DNA into the protein. AARS catalyse the attachment of amino acids to transfer RNAs and thereby establish the rules of the genetic code by virtue of matching the nucleotide triplet of the anticodon with its cognate amino acid. Here we summarise the effects of recent studies on this interesting family of multifunctional enzymes.
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Amino Acyl-tRNA Synthetases
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