Kinetic Partitioning between Synthetic and Editing Pathways in Class I Aminoacyl-tRNA Synthetases Occurs at Both Pre-transfer and Post-transfer Hydrolytic Steps

Cvetešić, Nevena; Perona, John J.; Gruić-Sovulj, Ita

doi:10.1074/jbc.m112.372151

Cited by 55 publications

(134 citation statements)

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“…Structural and kinetic analyses revealed that the large peptide fragment (connective peptide, CP1), inserted into the Rossmann fold catalytic domain, folds into a well defined domain dedicated to post-transfer editing (21)(22)(23)(24). IleRS shares this feature with homologous class Ia leucyl-and valyl-tRNA synthetases (LeuRS and ValRS, respectively) (25)(26)(27). Along with deacylation of valyl-tRNA Ile (Val-tRNA Ile ) at the CP1 domain, IleRS also displays a distinctive capacity to hydrolyze valyl-AMP in a tRNA-dependent manner within the synthetic site (12,28).…”

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confidence: 99%

The tRNA A76 Hydroxyl Groups Control Partitioning of the tRNA-dependent Pre- and Post-transfer Editing Pathways in Class I tRNA Synthetase

Cvetešić

Biluš

Gruić-Sovulj

2015

Journal of Biological Chemistry

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Background: Isoleucyl-tRNA synthetase uses cognate tRNA to stimulate hydrolysis of non-cognate aminoacyl-adenylates within the synthetic site. Results: The 3Ј-terminal hydroxyl groups of tRNA Ile have no role in pre-transfer editing. Conclusion: The tRNAIle body, rather than the 3Ј-end of tRNA Ile alone, promotes assembly of the improved ribonuclear protein synthetic site. Significance: Isoleucyl-tRNA synthetase acts as a ribonuclear protein to adjust amino acid recognition to the cellular environment.

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confidence: 99%

The tRNA A76 Hydroxyl Groups Control Partitioning of the tRNA-dependent Pre- and Post-transfer Editing Pathways in Class I tRNA Synthetase

Cvetešić

Biluš

Gruić-Sovulj

2015

Journal of Biological Chemistry

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“…In many cases, this activity seems to be enhanced in the presence of tRNA (20,21,23). Thus, in the evolution of LeuRS, IleRS, and ValRS, the original insertion of the CP1 domain likely affected fidelity via a set of mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…The balance of fidelity mechanisms that rely on post-or pretransfer editing can differ and shift (8,25). A preponderance of posttransfer editing versus pretransfer editing can be dictated by a rapid aminoacyl-transfer step in the aminoacylation site (22,23,41). Likewise, the CP1 domain in IleRS relies upon pretransfer editing as its dominant editing pathway (42) because of a slow transfer rate (22).…”

Section: Discussionmentioning

confidence: 99%

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Leucyl-tRNA synthetase editing domain functions as a molecular rheostat to control codon ambiguity in Mycoplasma pathogens

Palencia

Lukk³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Mycoplasma leucyl-tRNA synthetases (LeuRSs) have been identified in which the connective polypeptide 1 (CP1) amino acid editing domain that clears mischarged tRNAs are missing (Mycoplasma mobile) or highly degenerate (Mycoplasma synoviae). Thus, these enzymes rely on a clearance pathway called pretransfer editing, which hydrolyzes misactivated aminoacyl-adenylate intermediate via a nebulous mechanism that has been controversial for decades. Even as the sole fidelity pathway for clearing amino acid selection errors in the pathogenic M. mobile, pretransfer editing is not robust enough to completely block mischarging of tRNA Leu , resulting in codon ambiguity and statistical proteins. A high-resolution X-ray crystal structure shows that M. mobile LeuRS structurally overlaps with other LeuRS cores. However, when CP1 domains from different aminoacyl-tRNA synthetases and origins were fused to this common LeuRS core, surprisingly, pretransfer editing was enhanced. It is hypothesized that the CP1 domain evolved as a molecular rheostat to balance multiple functions. These include distal control of specificity and enzyme activity in the ancient canonical core, as well as providing a separate hydrolytic active site for clearing mischarged tRNA.protein evolution | quality control | statistical proteins | aminoacylation | translation

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“…Yet, our comprehensive work on the mechanism of pre-transfer editing proved the model wrong and demonstrated that pre-transfer editing reactions actually reside within the confines of the synthetic site. [48][49][50][51][52] SerRS was the highly important player in establishing this new pre-transfer editing model. as this enzyme, in all domains of life, naturally lacks a domain specialized in editing.…”

Section: Serrs: a Proofreading Enzyme Without The Error-correction Domentioning

confidence: 99%

Seryl-tRNA Synthetases in Translation and Beyond

Močibob¹,

Rokov-Plavec²,

Godinić-Mikulčić³

et al. 2016

Croat. Chem. Acta

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Abstract:For a long time seryl-tRNA synthetases (SerRSs) stood as an archetypal, canonical aminoacyl-tRNA synthetases (aaRS), exhibiting only basic tRNA aminoacylation activity and with no moonlighting functions beyond protein biosynthesis. The picture has changed substantially in recent years after the discovery that SerRSs play an important role in antibiotic production and resistance and act as a regulatory factor in vascular development, as well as after the discovery of mitochondrial morphogenesis factor homologous to SerRS in insects. In this review we summarize the recent research results from our laboratory, which advance the understanding of seryl-tRNA synthetases and further paint the dynamic picture of unexpected SerRS activities. SerRS from archaeon Methanothermobacter thermautotrophicus was shown to interact with the large ribosomal subunit and it was postulated to contribute to a more efficient translation by the"tRNA channeling" hypothesis. Discovery of the atypical SerRS in a small number of methanogenic archaea led to the discovery of a new family of enzymes in numerous bacteria -amino acid:[carrier protein] ligases (aa:CP ligases). These SerRS homologues resigned tRNA aminoacylation activity, and instead adopted carrier proteins as the acceptors of activated amino acids. The crystal structure of the aa:CP ligase complex with the carrier protein revealed that the interactions between two macromolecules are incomparable to tRNA binding by the aaRS and consequently represent a true evolutionary invention. Kinetic investigations of SerRSs and the accuracy of amino acid selection revealed that SerRSs possess pre-transfer proofreading activity, challenging the widely accepted presumption that hydrolytic proofreading activity must reside in an additional, separate editing domain, not present in SerRSs. Finally, the plant tRNA serylation system is discussed, which is particularly interesting due to the fact that protein biosynthesis takes place in three cellular compartments: cytosol, mitochondria and chloroplasts. Plant cytosolic SerRSs showed broad tRNA Ser specificity and flexibility, unlike SerRSs from other organisms. High fidelity of SerRS dually targeted to mitochondria and chloroplasts indicated its importance in plant organellar quality control.

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Kinetic Partitioning between Synthetic and Editing Pathways in Class I Aminoacyl-tRNA Synthetases Occurs at Both Pre-transfer and Post-transfer Hydrolytic Steps

Cited by 55 publications

References 72 publications

The tRNA A76 Hydroxyl Groups Control Partitioning of the tRNA-dependent Pre- and Post-transfer Editing Pathways in Class I tRNA Synthetase

The tRNA A76 Hydroxyl Groups Control Partitioning of the tRNA-dependent Pre- and Post-transfer Editing Pathways in Class I tRNA Synthetase

Leucyl-tRNA synthetase editing domain functions as a molecular rheostat to control codon ambiguity in Mycoplasma pathogens

Seryl-tRNA Synthetases in Translation and Beyond

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