scholarly journals Class I and II aminoacyl-tRNA synthetase tRNA groove discrimination created the first synthetase•tRNA cognate pairs and was therefore essential to the origin of genetic coding

2019 ◽  
Author(s):  
Charles W. Carter ◽  
Peter R. Wills
Keyword(s):  
Trna Synthetase ◽  
Class I ◽  
Stem Loop ◽  
Class Division ◽  
Trna Synthetases ◽  
Regression Methods ◽  
Genetic Coding ◽  
Base Sequences ◽  
Coding Rules ◽  
Necessary And Sufficient

ABSTRACTThe genetic code likely arose when a bidirectional gene began to produce ancestral aminoacyl-tRNA synthetases (aaRS) capable of distinguishing between two distinct sets of amino acids. The synthetase Class division therefore necessarily implies a mechanism by which the two ancestral synthetases could also discriminate between two different kinds of tRNA substrates. We used regression methods to uncover the possible patterns of base sequences capable of such discrimination and find that they appear to be related to thermodynamic differences in the relative stabilities of a hairpin necessary for recognition of tRNA substrates by Class I aaRS. The thermodynamic differences appear to be exploited by secondary structural differences between models for the ancestral aaRS called synthetase Urzymes and reinforced by packing of aromatic amino acid side chains against the nonpolar face of the ribose of A76 if and only if the tRNA CCA sequence forms a hairpin. The patterns of bases 1, 2 and 73 and stabilization of the hairpin by structural complementarity with Class I, but not Class II aaRS Urzymes appears to be necessary and sufficient to have enabled the generation of the first two aaRS•tRNA cognate pairs, and the launch of a rudimentary binary genetic coding related recognizably to contemporary cognate pairs. As a consequence, it seems likely that non-random aminoacylation of tRNAs preceded the advent of the tRNA anticodon stem-loop. Consistent with this suggestion, coding rules in the acceptor-stem bases also reveal a palimpsest of the codon•anticodon interaction, as previously proposed.

scholarly journals Inhibitory mechanism of reveromycin A at the tRNA binding site of a class I synthetase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Bingyi Chen ◽  
Siting Luo ◽  
Songxuan Zhang ◽  
Yingchen Ju ◽  
Qiong Gu ◽  
...  
Keyword(s):  
Binding Site ◽  
Catalytic Domain ◽  
Trna Synthetase ◽  
Rational Drug Design ◽  
Class I ◽  
Binding Assays ◽  
Trna Synthetases ◽  
Aminoacyl Trna Synthetases ◽  
Rational Drug ◽  
Trna Binding

AbstractThe polyketide natural product reveromycin A (RM-A) exhibits antifungal, anticancer, anti-bone metastasis, anti-periodontitis and anti-osteoporosis activities by selectively inhibiting eukaryotic cytoplasmic isoleucyl-tRNA synthetase (IleRS). Herein, a co-crystal structure suggests that the RM-A molecule occupies the substrate tRNAIle binding site of Saccharomyces cerevisiae IleRS (ScIleRS), by partially mimicking the binding of tRNAIle. RM-A binding is facilitated by the copurified intermediate product isoleucyl-adenylate (Ile-AMP). The binding assays confirm that RM-A competes with tRNAIle while binding synergistically with l-isoleucine or intermediate analogue Ile-AMS to the aminoacylation pocket of ScIleRS. This study highlights that the vast tRNA binding site of the Rossmann-fold catalytic domain of class I aminoacyl-tRNA synthetases could be targeted by a small molecule. This finding will inform future rational drug design.

scholarly journals Evidence that gene G7a in the human major histocompatibility complex encodes valyl-tRNA synthetase

1991 ◽  
Vol 278 (3) ◽  
pp. 809-816 ◽  
Author(s):  
S L Hsieh ◽  
R D Campbell
Keyword(s):  
Major Histocompatibility Complex ◽  
Amino Acid ◽  
Molecular Mass ◽  
Trna Synthetase ◽  
Class I ◽  
Major Histocompatibility ◽  
High Sequence Identity ◽  
Human Major Histocompatibility Complex ◽  
Trna Synthetases ◽  
Histocompatibility Complex

At least 36 genes have now been located in a 680 kb segment of DNA between the class I and class II multigene families within the class III region of the human major histocompatibility complex on chromosome 6p21.3. The complete nucleotide sequence of the 4.3 kb mRNA of one of these genes, G7a (or BAT6), has been determined from cDNA and genomic clones. The single-copy G7a gene encodes a 1265-amino-acid protein of molecular mass 140,457 Da. Comparison of the derived amino acid sequence of the G7a protein with the National Biomedical Research Foundation protein databases revealed 42% identity in a 250-amino-acid overlap with Bacillus stearothermophilus valyl-tRNA synthetase, 38.0% identity in a 993-amino-acid overlap with Escherichia coli valyl-tRNA synthetase (val RS), and 48.3% identity in a 1043-amino-acid overlap with Saccharomyces cerevisiae valyl-tRNA synthetase. The protein sequence of G7a contains two short consensus sequences, His-Ile-Gly-His and Lys-Met-Ser-Lys-Ser, which is the typical signature structure of class I tRNA synthetases and indicative of the presence of the Rossman fold. In addition, the molecular mass of the G7a protein is the same as that of other mammalian valyl-tRNA synthetases. These features and the high sequence identity with yeast valyl-tRNA synthetase strongly support the fact that the G7a gene, located within the major histocompatibility complex, encodes the human valyl-tRNA synthetase.

scholarly journals Interdependence, Reflexivity, Fidelity, Impedance Matching, and the Evolution of Genetic Coding

2017 ◽  
Author(s):  
Charles W. Carter ◽  
Peter Wills
Keyword(s):  
De Novo ◽  
Rna World ◽  
Impedance Matching ◽  
Error Rates ◽  
Ancestral Gene ◽  
Trna Synthetases ◽  
Translation Error ◽  
Genetic Coding ◽  
Necessary And Sufficient ◽  
Genetic Complementarity

ABSTRACTGenetic coding is generally thought to have required ribozymes whose functions were taken over by polypeptide aminoacyl-tRNA synthetases (aaRS). Two discoveries about aaRS and their tRNA substrates now furnish a unifying rationale for the opposite conclusion: that the key processes of the Central Dogma of molecular biology emerged simultaneously and naturally from simple origins in a peptide•RNA partnership, eliminating the epistemological need for a prior RNA world. First, the two aaRS classes likely arose from opposite strands of the same ancestral gene, implying a simple genetic alphabet. Inversion symmetries in aaRS structural biology arising from genetic complementarity would have stabilized the initial and subsequent differentiation of coding specificities and hence rapidly promoted diversity in the proteome. Second, amino acid physical chemistry maps onto tRNA identity elements, establishing reflexivity in protein aaRS. Bootstrapping of increasingly detailed coding is thus intrinsic to polypeptide aaRS, but impossible in an RNA world. These notions underline the following concepts that contradict gradual replacement of ribozymal aaRS by polypeptide aaRS: (i) any set of aaRS must be interdependent; (ii) reflexivity intrinsic to polypeptide aaRS production dynamics promotes bootstrapping; (iii) takeover of RNA-catalyzed aminoacylation by enzymes will necessarily degrade specificity; (iv) the Central Dogma’s emergence is most probable when replication and translation error rates remain comparable. These characteristics are necessary and sufficient for the essentially de novo emergence of a coupled gene-replicase-translatase system of genetic coding that would have continuously preserved the functional meaning of genetically encoded protein genes whose phylogenetic relationships match those observed today.

scholarly journals High-Resolution, Multidimensional Phylogenetic Metrics Identify Class I Aminoacyl-tRNA Synthetase Evolutionary Mosaicity and Inter-modular ‘Coupling

2020 ◽  
Author(s):  
Charles W. Carter ◽  
Alex Popinga ◽  
Remco Bouckaert ◽  
Peter R. Wills
Keyword(s):  
Amino Acid ◽  
Trna Synthetase ◽  
Class I ◽  
Evolutionary Divergence ◽  
Aminoacyl Trna Synthetase ◽  
Insertion Element ◽  
Sequence Alignments ◽  
Multiple Sequence ◽  
Residue Conservation ◽  
Genetic Coding

AbstractThe provenance of the aminoacyl-tRNA synthetases (aaRS) poses unusually challenging questions because of their role in the emergence and evolution of genetic coding. We investigate evidence about their ancestry from highly curated structure-based multiple sequence alignments of a small “scaffold” that is structurally invariant in all 10 canonical Class I aaRS. Statistically different values of two uncorrelated phylogenetic metrics—residue by residue conservation derived from Clustal and row-by-row cladistic congruence derived from BEAST2—suggest that the Class I scaffold is a mosaic assembled from distinct, successive genetic sources. These data are especially significant in light of: (i) experimental fragmentations of the Class I scaffold into three partitions that retain catalytic activities in proportion to their length; and (ii) multiple sources of evidence that two of these partitions arose from an ancestral Class I aaRS gene encoding a Class II ancestor in frame on the opposite strand. Two additional metrics output by BEAST2 vary in accordance with the presumed functionality endowed by the various modules. The new evidence supplements previous aaRS phylogenies. It identifies a previously characterized 46-residue Class I “protozyme” as preceding the adaptive radiation of the superfamily containing variations of the Rossmann dinucleotide binding fold related to amino acid discrimination, and thus as root of that molecular tree. Such a rooting is consistent with near simultaneous emergence of genetic coding and the origin of the proteome, resolving a conundrum posed by previous inferences that Class I aaRS evolved long after the genetic code had been implemented in an RNA world. Further, it establishes a timeline for the growth of coding from a binary amino acid alphabet by pinpointing discontinuous enhancements of aaRS fidelity.Author SummaryPhylogenetic analysis uncovers evolutionary connections between different protein superfamily members. We describe complementary, uncorrelated, phylogenetic metrics that support multiple evolutionary histories for different segments within members of the Class I aminoacyl-tRNA synthetase superfamily. Using a carefully curated 3D crystal structure superposition as the primary source of the multiple sequence alignment substantially reduced dependence of these metrics on empirical amino acid substitution matrices. Two metrics are derived from the amino acid distribution observed in each successive position. A third depends on how individual sequences distribute into phylogenetic tree branches for each of the ten amino acids activated by the superfamily. All metrics confirm that a segment previously identified as an inserted element is, indeed, a more recent acquisition, despite its structural conservation. The residue-by-residue conservation metrics reveal significant co-variation of mutational frequencies between a core segment that forms the amino acid binding site and a neighboring segment derived from the more recent insertion element. We attribute that covariation to the differentiation of superfamily members as evolutionary divergence enhanced amino acid specificity. Finally, evidence that the insertion element is a recent acquisition implies a new branching order for much of the proteome.

scholarly journals High-Resolution, Multidimensional Phylogenetic Metrics Identify Class I Aminoacyl-tRNA Synthetase Evolutionary Mosaicity and Inter-modular Coupling

2021 ◽  
Author(s):  
Charles Carter ◽  
Alex Popinga ◽  
Remco Bouckaert ◽  
Peter R Wills
Keyword(s):  
Rna World ◽  
Trna Synthetase ◽  
Class I ◽  
Sequence Alignments ◽  
Gene Encoding ◽  
Multiple Sequence ◽  
Multiple Sequence Alignments ◽  
Canonical Class ◽  
Genetic Coding ◽  
Molecular Tree

The provenance of the aminoacyl-tRNA synthetases (aaRS) poses challenging questions because of their role in the emergence and evolution of genetic coding. We investigate evidence about their ancestry from curated structure-based multiple sequence alignments of a structurally invariant “scaffold” shared by all 10 canonical Class I aaRS. Three uncorrelated phylogenetic metrics—residue-by-residue conservation, its variance, and row-by-row cladistic congruence—imply that the Class I scaffold is a mosaic assembled from distinct, successive genetic sources. These data are especially significant in light of: (i) experimental fragmentations of the Class I scaffold into three partitions that retain catalytic activities in proportion to their length; and (ii) evidence that two of these partitions arose from an ancestral Class I aaRS gene encoding a Class II ancestor in frame on the opposite strand. Phylogenetic metrics of different modules vary in accordance with their presumed functionality. A 46-residue Class I “protozyme” roots the Class I molecular tree prior to the adaptive radiation of the Rossmann dinucleotide binding fold that refined substrate discrimination. Such rooting is consistent with near simultaneous emergence of genetic coding and the origin of the proteome, resolving a conundrum posed by previous inferences that Class I aaRS evolved long after the genetic code had been implemented in an RNA world. Further, pinpointing discontinuous enhancements of aaRS fidelity establishes a timeline for the growth of coding from a binary amino acid alphabet.

The Roots of Genetic Coding in Aminoacyl-tRNA Synthetase Duality

2021 ◽  
Vol 90 (1) ◽  
Author(s):  
Charles W. Carter ◽  
Peter R. Wills
Keyword(s):  
Phase Transfer ◽  
Trna Synthetase ◽  
Annual Review ◽  
Publication Date ◽  
Free Energies ◽  
Transfer Rnas ◽  
Trna Synthetases ◽  
Genetic Codes ◽  
Genetic Coding ◽  
Trna Substrate

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. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals A tRNA- and Anticodon-Centric View of the Evolution of Aminoacyl-tRNA Synthetases, tRNAomes, and the Genetic Code

Life ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 37 ◽  
Author(s):  
Yunsoo Kim ◽  
Kristopher Opron ◽  
Zachary F. Burton
Keyword(s):  
Genetic Code ◽  
Class Ii ◽  
Trna Synthetase ◽  
Class I ◽  
Protein Fold ◽  
Standard Genetic Code ◽  
Structural Class ◽  
Trna Synthetases ◽  
Protein Fold Recognition ◽  
Coevolution Theory

Pathways of standard genetic code evolution remain conserved and apparent, particularly upon analysis of aminoacyl-tRNA synthetase (aaRS) lineages. Despite having incompatible active site folds, class I and class II aaRS are homologs by sequence. Specifically, structural class IA aaRS enzymes derive from class IIA aaRS enzymes by in-frame extension of the protein N-terminus and by an alternate fold nucleated by the N-terminal extension. The divergence of aaRS enzymes in the class I and class II clades was analyzed using the Phyre2 protein fold recognition server. The class I aaRS radiated from the class IA enzymes, and the class II aaRS radiated from the class IIA enzymes. The radiations of aaRS enzymes bolster the coevolution theory for evolution of the amino acids, tRNAomes, the genetic code, and aaRS enzymes and support a tRNA anticodon-centric perspective. We posit that second- and third-position tRNA anticodon sequence preference (C>(U~G)>A) powerfully selected the sectoring pathway for the code. GlyRS-IIA appears to have been the primordial aaRS from which all aaRS enzymes evolved, and glycine appears to have been the primordial amino acid around which the genetic code evolved.

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