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Quality control in tRNA charging

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Abstract Faithful translation of the genetic code during protein synthesis is fundamental to the growth, development, and function of living organisms. Aminoacyl‐tRNA synthetases (AARSs), which define the genetic code by correctly pairing amino acids with their cognate tRNAs, are responsible for ‘quality control’ in the flow of information from a gene to a protein. When differences in binding energies of amino acids to an AARS are inadequate, editing is used to achieve high selectivity. Editing occurs at the synthetic active site by hydrolysis of noncognate aminoacyl‐adenylates (pretransfer editing) and at a dedicated editing site located in a separate domain by deacylation of mischarged aminoacyl‐tRNA (posttransfer editing). Access of nonprotein amino acids, such as homocysteine or ornithine, to the genetic code is prevented by the editing function of AARSs, which functionally partitions amino acids present in living cells into protein and nonprotein amino acids. Continuous editing is part of the tRNA aminoacylation process in living organisms from bacteria to human beings. Preventing mistranslation by the clearance of misactivated amino acids is crucial to cellular homeostasis and has a role in etiology of disease. Although there is a strong selective pressure to minimize mistranslation, some organisms possess error‐prone AARSs that cause mistranslation. Elevated levels of mistranslation and the synthesis of statistical proteins can be beneficial for pathogens by increasing phenotypic variation essential for the evasion of host defenses. WIREs RNA 2012, 3:295–310. doi: 10.1002/wrna.122 This article is categorized under: RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution Translation > Translation Mechanisms RNA Processing > tRNA Processing RNA in Disease and Development > RNA in Disease

Editing pathways during tRNA aminoacylation. A cognate amino acid proceeds through the aminoacylation pathway, indicated by the double‐headed arrows, generating correctly charged AA‐tRNA. A noncognate amino acid enters the aminoacylation pathway but is cleared as indicated by single‐headed arrows; as a result, continuous hydrolysis of ATP to AMP occurs, a diagnostic feature of editing.10

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Schematic illustration of chemical modification of a protein lysine residue by Hcy‐thiolactone.118

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Editing of homocysteine, aminoacylation of thiols, and synthesis of S‐nitroso‐Hcy‐tRNAMet catalyzed by MetRS. Upper panel: The MetRS‐catalyzed cyclization of homocysteinyl‐adenylate to form Hcy‐thiolactone and AMP that are subsequently released from the synthetic/editing active site of MetRS. Middle panel: The MetRS catalyzed reaction of a thiol (mimicking the side chain of Hcy, R–CH2SH) with Met‐tRNAMet to form a Met thioester, which is subsequently released from the synthetic/editing active site of MetRS.34 Lower panel: MetRS‐catalyzed aminoacylation of tRNAMet with S‐nitroso‐Hcy.35

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Substrate‐assisted catalysis of hydrolytic deacylation of mischarged Ser‐tRNAThr in P. abyssi ThrRS editing domain57. The 2′ OH of the ribose acts as a general base and activates water molecule (W1) for a nucleophilic attack on the carbonyl carbon of the l‐Ser‐tRNAThr. The tetrahedral intermediate is stabilized by the oxyanion hole formed by the main chain nitrogen atom of Ala82 and main chain as well as side chain nitrogen atoms of His83.

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RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution
Translation > Translation Mechanisms
RNA in Disease and Development > RNA in Disease
RNA Processing > tRNA Processing

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