RNA versatility governs tRNA function: Why tRNA flexibility is essential beyond the translation cycle.
TL;DR: In analogy to tRNA surveillance, this review finds that other processes also exploit versatile tRNA folding to achieve, amongst others, specific aminoacylation, translational regulation by riboswitches or a block of bacterial translation.
Abstract: tRNAs undergo multiple conformational changes during the translation cycle that are required for tRNA translocation and proper communication between the ribosome and translation factors. Recent structural data on how destabilized tRNAs utilize the CCA-adding enzyme to proofread themselves put a spotlight on tRNA flexibility beyond the translation cycle. In analogy to tRNA surveillance, this review finds that other processes also exploit versatile tRNA folding to achieve, amongst others, specific aminoacylation, translational regulation by riboswitches or a block of bacterial translation. tRNA flexibility is thereby not restricted to the hinges utilized during translation. In contrast, the flexibility of tRNA is distributed all over its L-shape and is actively exploited by the tRNA-interacting partners to discriminate one tRNA from another. Since the majority of tRNA modifications also modulate tRNA flexibility it seems that cells devote enormous resources to tightly sense and regulate tRNA structure. This is likely required for error-free protein synthesis.
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TL;DR: The deposition of chemical modifications into RNA is a crucial regulator of temporal and spatial gene expression programs during development as discussed by the authors, and altered RNA modification patterns are widely linked to developmental diseases, and dysregulation of RNA modification pathways also emerged as a contributor to cancer.
Abstract: The deposition of chemical modifications into RNA is a crucial regulator of temporal and spatial gene expression programs during development. Accordingly, altered RNA modification patterns are widely linked to developmental diseases. Recently, the dysregulation of RNA modification pathways also emerged as a contributor to cancer. By modulating cell survival, differentiation, migration and drug resistance, RNA modifications add another regulatory layer of complexity to most aspects of tumourigenesis.
219 citations
04 Apr 2017
TL;DR: It was shown that tRNA modifications are important for temperature adaptation in thermophilic as well as psychrophilic organisms, as they modulate rigidity and flexibility of the transcripts, respectively.
Abstract: Transfer RNAs (tRNAs) are central players in translation, functioning as adapter molecules between the informational level of nucleic acids and the functional level of proteins. They show a highly conserved secondary and tertiary structure and the highest density of post-transcriptional modifications among all RNAs. These modifications concentrate in two hotspots—the anticodon loop and the tRNA core region, where the D- and T-loop interact with each other, stabilizing the overall structure of the molecule. These modifications can cause large rearrangements as well as local fine-tuning in the 3D structure of a tRNA. The highly conserved tRNA shape is crucial for the interaction with a variety of proteins and other RNA molecules, but also needs a certain flexibility for a correct interplay. In this context, it was shown that tRNA modifications are important for temperature adaptation in thermophilic as well as psychrophilic organisms, as they modulate rigidity and flexibility of the transcripts, respectively. Here, we give an overview on the impact of modifications on tRNA structure and their importance in thermal adaptation.
217 citations
Cites background from "RNA versatility governs tRNA functi..."
...While interacting with other molecules, like T-box elements or aminoacyl-tRNA synthetases, the tRNA slightly adapts its structure, reflecting the need for a certain flexibility (reviewed in [7,16])....
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TL;DR: The post-transcriptional modifications of tRNA's anticodon domain are the most diverse and chemically complex of any RNA modifications and reveal individual and combined effects on tRNA function in recognition of cognate and wobble codons.
Abstract: A simple post-transcriptional modification of tRNA, deamination of adenosine to inosine at the first, or wobble, position of the anticodon, inspired Francis Crick's Wobble Hypothesis 50 years ago. ...
123 citations
Cites background from "RNA versatility governs tRNA functi..."
...t(6)A37 also facilitates ribosomal codon binding and maintains the translational frame.(26,126)...
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...Other modifications at position 37, particularly in tRNAs responding to codons beginning with U, UNN, such as wyosine, contribute similarly to base stacking, maintaining the open loop structure and by doing so maintain the translational reading frame.(26,126) The fact that the ASL can be stabilized by various purine 37 modifications implies convergent evolutionary pathways that relate not only to the identity of the codon, but also to that of the nucleoside at position 34 and perhaps additionally either 32 or 38/39....
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TL;DR: An update on the latest findings regarding tRNA quality control that turns out to represent an interplay of the CCA-adding enzyme and RNases involved in tRNA degradation and maturation is given.
39 citations
01 Apr 2016
TL;DR: Comparing and contrast the molecular ruler characteristics of the RNase P ribozyme and the T-box riboswitch may augur the discovery of new RNA measuring devices in noncoding and viral transcriptomes, and inform the design of artificial RNA rulers.
Abstract: Length determination is a fundamental problem in biology and chemistry. Numerous proteins measure distances on linear biopolymers to exert effects with remarkable spatial precision. Recently, ruler-like devices made of noncoding RNAs have been structurally and biochemically characterized. Two prominent examples are the RNase P ribozyme and the T-box riboswitch. Both act as molecular calipers. The two RNAs clamp onto the elbow of tRNA (or pre-tRNA) and make distance measurements orthogonal to each other. Here, we compare and contrast the molecular ruler characteristics of these RNAs. RNase P appears pre-configured to measure a fixed distance on pre-tRNA to ensure the fidelity of its maturation. RNase P is a multiple-turnover ribozyme, and its rigid structure efficiently selects pre-tRNAs, cleaves, and releases them. In contrast, the T-box is flexible and segmented, an architecture that adapts to the intrinsically flexible tRNA. The tripartite T-box inspects the overall shape, anticodon sequence, and aminoacylation status of an incoming tRNA while it folds co-transcriptionally, leading to a singular, conditional genetic switching event. The elucidation of the structures and mechanisms of action of these two RNA molecular rulers may augur the discovery of new RNA measuring devices in noncoding and viral transcriptomes, and inform the design of artificial RNA rulers.
16 citations
References
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TL;DR: It is established that the ribosome is a ribozyme and the catalytic properties of its all-RNA active site are addressed and the mechanism of peptide bond synthesis appears to resemble the reverse of the acylation step in serine proteases.
Abstract: Using the atomic structures of the large ribosomal subunit from Haloarcula marismortui and its complexes with two substrate analogs, we establish that the ribosome is a ribozyme and address the catalytic properties of its all-RNA active site. Both substrate analogs are contacted exclusively by conserved ribosomal RNA (rRNA) residues from domain V of 23S rRNA; there are no protein side-chain atoms closer than about 18 angstroms to the peptide bond being synthesized. The mechanism of peptide bond synthesis appears to resemble the reverse of the acylation step in serine proteases, with the base of A2486 (A2451 in Escherichia coli) playing the same general base role as histidine-57 in chymotrypsin. The unusual pK(a) (where K(a) is the acid dissociation constant) required for A2486 to perform this function may derive in part from its hydrogen bonding to G2482 (G2447 in E. coli), which also interacts with a buried phosphate that could stabilize unusual tautomers of these two bases. The polypeptide exit tunnel is largely formed by RNA but has significant contributions from proteins L4, L22, and L39e, and its exit is encircled by proteins L19, L22, L23, L24, L29, and L31e.
2,187 citations
TL;DR: The crystal structure of the bacterial 70S ribosome refined to 2.8 angstrom resolution reveals atomic details of its interactions with messenger RNA (mRNA) and transfer RNA (t RNA) and metal ions also stabilize the intersubunit interface.
Abstract: The crystal structure of the bacterial 70S ribosome refined to 2.8 angstrom resolution reveals atomic details of its interactions with messenger RNA (mRNA) and transfer RNA (tRNA). A metal ion stabilizes a kink in the mRNA that demarcates the boundary between A and P sites, which is potentially important to prevent slippage of mRNA. Metal ions also stabilize the intersubunit interface. The interactions of E-site tRNA with the 50S subunit have both similarities and differences compared to those in the archaeal ribosome. The structure also rationalizes much biochemical and genetic data on translation.
1,312 citations
TL;DR: The complete nucleotide sequence of an alanine transfer RNA, isolated from yeast, has been determined and is the first nucleic acid for which the structure is known.
Abstract: The complete nucleotide sequence of an alanine transfer RNA, isolated from yeast, has been determined. This is the first nucleic acid for which the structure is known.
1,131 citations
TL;DR: The structure of a tRNA has been determined by isomorphous replacement but the interactions which maintain the tertiary structure are of a novel type and this model differs significantly from one which has recently been proposed.
Abstract: The structure of a tRNA has been determined by isomorphous replacement. Some of the interactions which maintain the tertiary structure are of a novel type. Our model differs significantly from one which has recently been proposed.
901 citations
TL;DR: How the interaction between structural and functional studies over the last decade has led to a deeper understanding of the complex mechanisms underlying translation is discussed.
Abstract: The high-resolution structures of ribosomal subunits published in 2000 have revolutionized the field of protein translation They facilitated the determination and interpretation of functional complexes of the ribosome by crystallography and electron microscopy Knowledge of the precise positions of residues in the ribosome in various states has facilitated increasingly sophisticated biochemical and genetic experiments, as well as the use of new methods such as single-molecule kinetics In this review, we discuss how the interaction between structural and functional studies over the last decade has led to a deeper understanding of the complex mechanisms underlying translation
659 citations