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At least 469 records · Page 26Linked to original sources
PubMed2002

Towards structural genomics of RNA: rapid NMR resonance assignment and simultaneous RNA tertiary structure determination using residual dipolar couplings.

We report a new residual dipolar couplings (RDCs) based NMR procedure for rapidly determining RNA tertiary structure demonstrated on a uniformly (15)N/(13)C-labeled 27 nt variant of the trans-activation response element (TAR) RNA from HIV-I. In this procedure, the time-consuming nuclear Overhauser enhancement (NOE)-based sequential assignment step is replaced by a fully automated RDC-based assignment strategy. This approach involves examination of all allowed sequence-specific resonance assignment permutations for best-fit agreement between measured RDCs and coordinates for sub-structures in a target RNA. Using idealized A-form geometries to model Watson-Crick helices and coordinates from a previous X-ray structure to model a hairpin loop in TAR, the best-fit RDC assignment solutions are determined very rapidly (<five minutes of computational time) and are in complete agreement with corresponding NOE-based assignments. Orientational constraints derived from RDCs are used simultaneously to assemble sub-structures into an RNA tertiary conformation. Through enhanced speeds of application and reduced reliance on chemical shift dispersion, this RDC-based approach lays the foundation for rapidly determining RNA conformations in a structural genomics context, and may increase the size limit of RNAs that can be examined by NMR.

Base Sequence↗
PubMed2005

Mapping of conserved RNA secondary structures predicts thousands of functional noncoding RNAs in the human genome.

In contrast to the fairly reliable and complete annotation of the protein coding genes in the human genome, comparable information is lacking for noncoding RNAs (ncRNAs). We present a comparative screen of vertebrate genomes for structural noncoding RNAs, which evaluates conserved genomic DNA sequences for signatures of structural conservation of base-pairing patterns and exceptional thermodynamic stability. We predict more than 30,000 structured RNA elements in the human genome, almost 1,000 of which are conserved across all vertebrates. Roughly a third are found in introns of known genes, a sixth are potential regulatory elements in untranslated regions of protein-coding mRNAs and about half are located far away from any known gene. Only a small fraction of these sequences has been described previously. A comparison with recent tiling array data shows that more than 40% of the predicted structured RNAs overlap with experimentally detected sites of transcription. The widespread conservation of secondary structure points to a large number of functional ncRNAs and cis-acting mRNA structures in the human genome.

Animals↗
PubMed1998

The 5S rRNA loop E: chemical probing and phylogenetic data versus crystal structure.

A significant fraction of the bases in a folded, structured RNA molecule participate in noncanonical base pairing interactions, often in the context of internal loops or multi-helix junction loops. The appearance of each new high-resolution RNA structure provides welcome data to guide efforts to understand and predict RNA 3D structure, especially when the RNA in question is a functionally conserved molecule. The recent publication of the crystal structure of the "Loop E" region of bacterial 5S ribosomal RNA is such an event [Correll CC, Freeborn B, Moore PB, Steitz TA, 1997, Cell 91:705-712]. In addition to providing more examples of already established noncanonical base pairs, such as purine-purine sheared pairings, trans-Hoogsteen UA, and GU wobble pairs, the structure provides the first high-resolution views of two new purine-purine pairings and a new GU pairing. The goal of the present analysis is to expand the capabilities of both chemical probing and phylogenetic analysis to predict with greater accuracy the structures of RNA molecules. First, in light of existing chemical probing data, we investigate what lessons could be learned regarding the interpretation of this widely used method of RNA structure probing. Then we analyze the 3D structure with reference to molecular phylogeny data (assuming conservation of function) to discover what alternative base pairings are geometrically compatible with the structure. The comparisons between previous modeling efforts and crystal structures show that the intricate involvements of ions and water molecules in the maintenance of non-Watson-Crick pairs render the process of correctly identifying the interacting sites in such pairs treacherous, except in cases of trans-Hoogsteen A/U or sheared A/G pairs for the adenine N1 site. The phylogenetic analysis identifies A/A, A/C, A/U and C/A, C/C, and C/U pairings isosteric with sheared A/G, as well as A/A and A/C pairings isosteric with both G/U and G/G bifurcated pairings. Thus, each non-Watson-Crick pair could be characterized by a phylogenetic signature of variations between isosteric-like pairings. In addition to the conservative changes, which form a dictionary of pairings isosterically compatible with those observed in the crystal structure, concerted changes involving several base pairs also occur. The latter covariations may indicate transitions between related but distinctive motifs within the loop E of 5S ribosomal RNA.

Bacteria↗
PubMedDate not supplied

[Search for alternative secondary structures of RNA, regulating expression of bacterial genes].

Expression of many bacterial genes is regulated by formation of alternative secondary RNA structure within the leader mRNA sequence. Our algorithm designed to search for these structures (basing on analysis of one nucleotide sequence) was applied to analyze operons of amino acid biosynthesis in alpha- and gamma-proteobacteria. The attenuators of these operons are predicted for genomes of some poorly known gamma-proteobacteria including Shewanella putrefaciens, attenuators of the tryptophan operon in some alpha-proteobacteria are also predicted.

Base Sequence↗
PubMed2006

Revolutions in RNA secondary structure prediction.

RNA structure formation is hierarchical and, therefore, secondary structure, the sum of canonical base-pairs, can generally be predicted without knowledge of the three-dimensional structure. Secondary structure prediction algorithms evolved from predicting a single, lowest free energy structure to their current state where statistics can be determined from the thermodynamic ensemble. This article reviews the free energy minimization technique and the salient revolutions in the dynamic programming algorithm methods for secondary structure prediction. Emphasis is placed on highlighting the recently developed method, which statistically samples structures from the complete Boltzmann ensemble.

Algorithms↗
PubMed2026

UFold-X: an enhanced Dual & Dynamic U-Mamba model for long-range RNA secondary structure prediction.

RNA secondary structure is essential for understanding the functions of non-coding RNAs, ribosomal RNAs, and viral genomes. However, accurate prediction of long RNA structures remains challenging due to complex long-range interactions and the limited availability of long-RNA training data. We present UFold-X, a dual-branch deep learning framework that combines a convolutional encoder for local structure modeling with a Mamba-based Visual State Space Module for capturing long-range dependencies. A dynamic gating mechanism adaptively integrates the two branches according to sequence length. UFold-X was evaluated on multiple benchmark datasets containing RNAs up to 5000 nucleotides. To rigorously assess generalization, we introduced a cross-clan benchmark for long RNAs. Under this stringent setting, UFold-X achieved performance comparable to state-of-the-art classical approaches while achieving the best performance among deep learning-based methods. Additional cross-family and within-family evaluations further demonstrated robust transferability and competitive predictive performance. UFold-X also maintained excellent computational efficiency, requiring only 0.08 s per sequence on average. To assess biological consistency, we developed a SHAPE-based reactivity prediction variant (UFold-X-R) and an integrated metric, the Hybrid Reactivity-Pairing Score (HRPS). UFold-X-R showed strong agreement with experimental icSHAPE data and achieved the highest HRPS among all evaluated methods. A user-friendly web server is available at https://ufold-x.ai4bread.com.

Nucleic Acid Conformation↗
PubMed1995

RNA-d2: a computer program for editing and display of RNA secondary structures.

RNA-d2 is a user-friendly program developed for interactively generating aesthetic and non-overlapping drawings of RNA secondary structures. It designed so that the drawings can be edited in a very natural and intuitive way, in order to emphasize structural homologies between several molecules, as well as the foldings themselves to update the base-pair sets according to new data. The program automatically produces a polygonal display in which the unpaired nucleotides are regularly positioned on circles and the stems harmoniously distributed on their periphery. RNA secondary structures can be encoded via the keyboard, but the program also automatically draws output files from thermodynamic prediction programs. The user interacts directly on different screen displays according to the editing functions. Rotation/translation of any subdomain and deletion of stems are performed on a coloured backbone view to make easier the identification of structural features, whereas addition of new base-pairings and numbering manipulation are realized on a complete polygonal view. Each modification is displayed in real time on the screen. When the display is obscured by numerous overlaps despite the colour code of the backbone view, an automatic function progressively straightens the subdomains which are highly compacted by very dissymmetric internal loops. RNA-d2 allows easy untangling and editing of RNA molecules > 1000 nucleotides long.

Algorithms↗
PubMed2005

The application of cluster analysis in the intercomparison of loop structures in RNA.

We have developed a computational approach for the comparison and classification of RNA loop structures. Hairpin or interior loops identified in atomic resolution RNA structures were intercompared by conformational matching. The root-mean-square deviation (RMSD) values between all pairs of RNA fragments of interest, even if from different molecules, are calculated. Subsequently, cluster analysis is performed on the resulting matrix of RMSD distances using the unweighted pair group method with arithmetic mean (UPGMA). The cluster analysis objectively reveals groups of folds that resemble one another. To demonstrate the utility of the approach, a comprehensive analysis of all the terminal hairpin tetraloops that have been observed in 15 RNA structures that have been determined by X-ray crystallography was undertaken. The method found major clusters corresponding to the well-known GNRA and UNCG types. In addition, two tetraloops with the unusual primary sequence UMAC (M is A or C) were successfully assigned to the GNRA cluster. Larger loop structures were also examined and the clustering results confirmed the occurrence of variations of the GNRA and UNCG tetraloops in these loops and provided a systematic means for locating them. Nineteen examples of larger loops that closely resemble either the GNRA or UNCG tetraloop were found in the large ribosomal RNAs. When the clustering approach was extended to include all structures in the SCOR database, novel relationships were detected including one between the ANYA motif and a less common folding of the GAAA tetraloop sequence.

Cluster Analysis↗
PubMed2003

Analysis of RNA motifs.

RNA motifs are directed and ordered stacked arrays of non-Watson-Crick base pairs forming distinctive foldings of the phosphodiester backbones of the interacting RNA strands. They correspond to the 'loops' - hairpin, internal and junction - that intersperse the Watson-Crick two-dimensional helices as seen in two-dimensional representations of RNA structure. RNA motifs mediate the specific interactions that induce the compact folding of complex RNAs. RNA motifs also constitute specific protein or ligand binding sites. A given motif is characterized by all the sequences that fold into essentially identical three-dimensional structures with the same ordered array of isosteric non-Watson-Crick base pairs. It is therefore crucial, when analyzing a three-dimensional RNA structure in order to identify and compare motifs, to first classify its non-Watson-Crick base pairs geometrically.

Base Pairing↗
PubMed2003

GPRM: A genetic programming approach to finding common RNA secondary structure elements.

RNA molecules play an important role in many biological activities. Knowing its secondary structure can help us better understand the molecule's ability to function. The methods for RNA structure determination have traditionally been implemented through biochemical, biophysical and phylogenetic analyses. As the advance of computer technology, an increasing number of computational approaches have recently been developed. They have different goals and apply various algorithms. For example, some focus on secondary structure prediction for a single sequence; some aim at finding a global alignment of multiple sequences. Some predict the structure based on free energy minimization; some make comparative sequence analyses to determine the structure. In this paper, we describe how to correctly use GPRM, a genetic programming approach to finding common secondary structure elements in a set of unaligned coregulated or homologous RNA sequences. GPRM can be accessed at http://bioinfo.cis.nctu.edu.tw/service/gprm/.

Internet↗
PubMed1998

Crystal structure of RNA helicase from genotype 1b hepatitis C virus. A feasible mechanism of unwinding duplex RNA.

Crystal structure of RNA helicase domain from genotype 1b hepatitis C virus has been determined at 2.3 A resolution by the multiple isomorphous replacement method. The structure consists of three domains that form a Y-shaped molecule. One is a NTPase domain containing two highly conserved NTP binding motifs. Another is an RNA binding domain containing a conserved RNA binding motif. The third is a helical domain that contains no beta-strand. The RNA binding domain of the molecule is distinctively separated from the other two domains forming an interdomain cleft into which single stranded RNA can be modeled. A channel is found between a pair of symmetry-related molecules which exhibit the most extensive crystal packing interactions. A stretch of single stranded RNA can be modeled with electrostatic complementarity into the interdomain cleft and continuously through the channel. These observations suggest that some form of this dimer is likely to be the functional form that unwinds double stranded RNA processively by passing one strand of RNA through the channel and passing the other strand outside of the dimer. A "descending molecular see-saw" model is proposed that is consistent with directionality of unwinding and other physicochemical properties of RNA helicases.

Acid Anhydride Hydrolases↗
PubMed2004

Spectral decomposition for the search and analysis of RNA secondary structure.

Scales in RNA, based on geometrical considerations, can be exploited for the analysis and prediction of RNA structures. By using spectral decomposition, geometric information that relates to a given RNA fold can be reduced to a single positive scalar number, the second eigenvalue of the Laplacian matrix corresponding to the tree-graph representation of the RNA secondary structure. Along with the free energy of the structure, being the most important scalar number in the prediction of RNA folding by energy minimization methods, the second eigenvalue of the Laplacian matrix can be used as an effective signature for locating a target folded structure given a set of RNA folds. Furthermore, the second eigenvector of the Laplacian matrix can be used to partition large RNA structures into smaller fragments. An illustrative example is given for the use of the second eigenvalue to predict mutations that may cause structural rearrangements, thereby disrupting stable motifs.

Archaea↗
PubMed2005

A method for aligning RNA secondary structures and its application to RNA motif detection.

BACKGROUND: Alignment of RNA secondary structures is important in studying functional RNA motifs. In recent years, much progress has been made in RNA motif finding and structure alignment. However, existing tools either require a large number of prealigned structures or suffer from high time complexities. This makes it difficult for the tools to process RNAs whose prealigned structures are unavailable or process very large RNA structure databases. RESULTS: We present here an efficient tool called RSmatch for aligning RNA secondary structures and for motif detection. Motivated by widely used algorithms for RNA folding, we decompose an RNA secondary structure into a set of atomic structure components that are further organized by a tree model to capture the structural particularities. RSmatch can find the optimal global or local alignment between two RNA secondary structures using two scoring matrices, one for single-stranded regions and the other for double-stranded regions. The time complexity of RSmatch is O(mn) where m is the size of the query structure and n that of the subject structure. When applied to searching a structure database, RSmatch can find similar RNA substructures, and is capable of conducting multiple structure alignment and iterative database search. Therefore it can be used to identify functional RNA motifs. The accuracy of RSmatch is tested by experiments using a number of known RNA structures, including simple stem-loops and complex structures containing junctions. CONCLUSION: With respect to computing efficiency and accuracy, RSmatch compares favorably with other tools for RNA structure alignment and motif detection. This tool shall be useful to researchers interested in comparing RNA structures obtained from wet lab experiments or RNA folding programs, particularly when the size of the structure dataset is large.

Algorithms↗
PubMed2006

Structural basis for RNA unwinding by the DEAD-box protein Drosophila Vasa.

DEAD-box RNA helicases, which regulate various processes involving RNA, have two RecA-like domains as a catalytic core to alter higher-order RNA structures. We determined the 2.2 A resolution structure of the core of the Drosophila DEAD-box protein Vasa in complex with a single-stranded RNA and an ATP analog. The ATP analog intensively interacts with both of the domains, thereby bringing them into the closed form, with many interdomain interactions of conserved residues. The bound RNA is sharply bent, avoiding a clash with a conserved alpha helix in the N-terminal domain. This "wedge" helix should disrupt base pairs by bending one of the strands when a duplex is bound. Mutational analyses indicated that the interdomain interactions couple ATP hydrolysis to RNA unwinding, probably through fine positioning of the duplex relative to the wedge helix. This mechanism, which differs from those for canonical translocating helicases, may enable the targeted modulation of intricate RNA structures.

Adenosine Triphosphate↗
PubMed2003

Mitochondrial RNase P RNAs in ascomycete fungi: lineage-specific variations in RNA secondary structure.

The RNA subunit of mitochondrial RNase P (mtP-RNA) is encoded by a mitochondrial gene (rnpB) in several ascomycete fungi and in the protists Reclinomonas americana and Nephroselmis olivacea. By searching for universally conserved structural elements, we have identified previously unknown rnpB genes in the mitochondrial DNAs (mtDNAs) of two fission yeasts, Schizosaccharomyces pombe and Schizosaccharomyces octosporus; in the budding yeast Pichia canadensis; and in the archiascomycete Taphrina deformans. The expression of mtP-RNAs of the predicted size was experimentally confirmed in the two fission yeasts, and their precise 5' and 3' ends were determined by sequencing of cDNAs generated from circularized mtP-RNAs. Comparative RNA secondary structure modeling shows that in contrast to mtP-RNAs of the two protists R. americana and N. olivacea, those of ascomycete fungi all have highly reduced secondary structures. In certain budding yeasts, such as Saccharomycopsis fibuligera, we find only the two most conserved pairings, P1 and P4. A P18 pairing is conserved in Saccharomyces cerevisiae and its close relatives, whereas nearly half of the minimum bacterial consensus structure is retained in the RNAs of fission yeasts, Aspergillus nidulans and Taphrina deformans. The evolutionary implications of the reduction of mtP-RNA structures in ascomycetes will be discussed.

Ascomycota↗
PubMed1993

Translational repression by the bacteriophage T4 gene 32 protein involves specific recognition of an RNA pseudoknot structure.

An RNA pseudoknot has been shown to form the 5'-end of bacteriophage T4 gene 32 mRNA that is essential to autoregulation of gene 32 (g32) mRNA by gene product 32 (gp32), a single-stranded nucleic acid binding protein. Structure-mapping of RNA oligonucleotides with structure-specific RNases indicate that two stem regions consisting of nucleotides -67 to -64 base-paired to -52 to -55 (stem-1) and nucleotides -62 to -56 base-paired to -40 to -46 (stem-2) can fold into a "pseudoknotted" structure that may be analogous to the semi-continuous a-helical pseudoknot. Our results suggest that the g32 mRNA pseudoknot can form under conditions where specific autoregulation by gp32 is observed. Although the g32 mRNA pseudoknot is stabilized by Mg2+, it exists in equilibrium with a 3'-hairpin structure. Gel mobility studies carried out with defined length oligonucleotides indicate the gp32 does, in fact, bind tightly to the pseudoknot. These studies agree with the proposal of McPheeters et al., that the pseudoknot represents a nucleation site essential for autogenous gp32 translation regulation. Although disruption of tertiary structure interactions in this pseudoknot (with EDTA) significantly reduces the ability of gp32 to specifically recognize its own mRNA, in vitro mutagenesis studies suggest the sequence of stem-2 and of the loop region (nucleotides -47 to -50) also represent important determinants for specific gp32 autoregulation. Based on a competition assay relying on gel mobility shifts, the order of importance of the major elements of the pseudoknot are stem-1 > sequence of stem-2 or loop-2 > stem-2. In this assay, disruption of stem-1 decreased the ability of the resulting structure to compete for gp32 binding by approximately fourfold. Both stem-1 and stem-2 appear to be essential to maintain high-level expression from gp32 mRNA in an in vitro transcription/translation system. Taken together, these results support the translation control model in which the pseudoknot region is a nucleation point for cooperative gp32 binding, which then proceeds in a 3' direction through a long stretch of single-stranded RNA that includes the initiation codon for gene 32.

Bacteriophage T4↗
PubMed2007

Structures of RNA switches: insight into molecular recognition and tertiary structure.

RNA switches (riboswitches) have important functions in gene regulation. They comprise an aptamer domain, which is responsible for ligand binding, and an expression platform that transmits the ligand-binding state of the aptamer domain through a conformational change. Riboswitches can regulate gene expression either at the level of transcription or translation, and it has been proposed that riboswitch mechanisms are even used to regulate the processing of mRNA. This Minireview summarizes the current understanding of the structures and mode of action of RNA switches, with particular focus on secondary and tertiary interactions, which stabilize the global RNA structure and thus determine the function of the aptamer domain.

Nucleic Acid Conformation↗
PubMed1997

Generation of coronavirus spike deletion variants by high-frequency recombination at regions of predicted RNA secondary structure.

Coronavirus RNA evolves in the central nervous systems (CNS) of mice during persistent infection. This evolution can be monitored by detection of a viral quasispecies of spike deletion variants (SDVs) (C. L. Rowe, S. C. Baker, M. J. Nathan, and J. O. Fleming, J. Virol. 71:2959-2969, 1997). We and others have found that the deletions cluster in the region from 1,200 to 1,800 nucleotides from the 5' end of the spike gene sequence, termed the "hypervariable" region. To address how SDVs might arise, we generated the predicted folding structures of the positive- and negative-strand senses of the entire 4,139-nt spike RNA sequence. We found that a prominent, isolated stem-loop structure is coincident with the hypervariable region in each structure. To determine if this predicted stem-loop is a "hot spot" for RNA recombination, we assessed whether this region of the spike is more frequently deleted than three other selected regions of the spike sequence in a population of viral sequences isolated from the CNS of acutely and persistently infected mice. Using differential colony hybridization of cloned spike reverse transcription-PCR products, we detected SDVs in which the hot spot was deleted but did not detect SDVs in which other regions of the spike sequence were exclusively deleted. Furthermore, sequence analysis and mapping of the crossover sites of 25 distinct patterns of SDVs showed that the majority of crossover sites clustered to two regions at the base of the isolated stem-loop, which we designated as high-frequency recombination sites 1 and 2. Interestingly, the majority of the left and right crossover sites of the SDVs were directly across from or proximal to one another, suggesting that these SDVs are likely generated by intramolecular recombination. Overall, our results are consistent with there being an important role for the spike RNA secondary structure as a contributing factor in the generation of SDVs during persistent infection.

Base Sequence↗