Sequential Folding of the Genomic Ribozyme of the Hepatitis Delta Virus: Structural Analysis of RNA Transcription Intermediates

Matysiak, Marcin; Wrzesiński, Jan; Ciesiołka, Jerzy

doi:10.1006/jmbi.1999.2955

Cited by 43 publications

(38 citation statements)

References 42 publications

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“…Concentrating on its folding paths, we identify (i) a transient kinetic trap that dominates quenched folding and (ii) a succession of transient stems that cooperatively guide sequential folding. Our quantitative predictions, which could be directly tested experimentally (8,9), largely support the suggestion that sequential folding kinetics of the HDV ribozyme directly regulate its in vivo function (7,10), a feature also suspected for other ribozymes (1,11).…”

supporting

confidence: 75%

“…The HDV ribozyme and its attenuator sequence are appealing test cases for our algorithm because extensive kinetic data exist for the native sequence as well as many mutants (7,8); the functional self-cleaving ribozyme is pseudoknotted (Fig. 4a) and active in vitro; and the alternative nonenzymatic conformation, once paired with the attenuator (Fig.…”

Section: Results: Folding Paths and Regulation Of The Hdv Ribozymementioning

confidence: 99%

“…But numbers such as individual kinetic rates and the overall folding time can easily be off by a factor of 10. Still, simulations promise to be an important adjunct to the many detailed studies of RNA folding now underway (8,9), as they can reach comparable times and rapidly generate hypothesis as to how sequence changes affect structure and kinetics, in particular transient guiding stems on the folding path.…”

Section: Discussionmentioning

confidence: 99%

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Modeling RNA folding paths with pseudoknots: Application to hepatitis delta virus ribozyme

Isambert

Siggia

2000

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

177

208

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A quantitative understanding of nucleic acid hybridization is essential to many aspects of biotechnology, such as DNA microarrays, as well as to the structure and folding kinetics of RNA. However, predictions of nucleic acid secondary structures have long been impeded by the presence of helices interior to loops, so-called pseudoknots, which impose complex three-dimensional conformational constraints. In this paper we compute the pseudoknot free energies analytically in terms of known standard parameters, and we show how the results can be included in a kinetic Monte Carlo code to follow the succession of secondary structures during quenched or sequential folding. For the hepatitis delta virus ribozyme, we predict several nonnative stems on the folding path, characterize a kinetically trapped state, interpret several experimentally characterized mutations in terms of the folding path, and suggest how hybridization with other parts of the genome inactivates the newly formed ribozyme.

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supporting

confidence: 75%

Section: Results: Folding Paths and Regulation Of The Hdv Ribozymementioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Modeling RNA folding paths with pseudoknots: Application to hepatitis delta virus ribozyme

Isambert

Siggia

2000

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

177

208

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“…12 P2 is proposed to form prior to the remaining HDV ribozyme and activate both genomic and antigenomic ribozyme, which may explain the resultant inactive conformation. 12,79,80 Alt1 is a 10-bp LDI formed between an upstream inhibitory stretch (nt ¡25/-15 related to the cleavage site) and the downstream stretch (nt 76/86). 12,81,82 Alt2 is an interaction between upstream flanking sequence and the ribozyme, and Alt3 is a non-native ribozyme-ribozyme interaction.…”

Section: Hdv Ribozymementioning

confidence: 99%

Four RNA families with functional transient structures

Zhu

Meyer

2015

RNA Biology

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P rotein-coding and non-coding RNA transcripts perform a wide variety of cellular functions in diverse organisms. Several of their functional roles are expressed and modulated via RNA structure. A given transcript, however, can have more than a single functional RNA structure throughout its life, a fact which has been previously overlooked. Transient RNA structures, for example, are only present during specific time intervals and cellular conditions. We here introduce four RNA families with transient RNA structures that play distinct and diverse functional roles. Moreover, we show that these transient RNA structures are structurally well-defined and evolutionarily conserved. Since RFAM annotates one structure for each family, there is either no annotation for these transient structures or no such family. Thus, our alignments either significantly update and extend the existing RFAM families or introduce a new RNA family to RFAM. For each of the four RNA families, we compile a multiplesequence alignment based on experimentally verified transient and dominant (dominant in terms of either the thermodynamic stability and/or attention received so far) RNA secondary structures using a combination of automated search via covariance model and manual curation. The first alignment is the Trp operon leader which regulates the operon transcription in response to tryptophan abundance through alternative structures. The second alignment is the HDV ribozyme which we extend to the 5 0 flanking sequence. This flanking sequence is involved in the regulation of the transcript's self-cleavage activity. The third alignment is the 5 0 UTR of the maturation protein from Levivirus which contains a transient structure that temporarily postpones the formation of the final inhibitory structure to allow translation of maturation protein. The fourth and last alignment is the SAM riboswitch which regulates the downstream gene expression by assuming alternative structures upon binding of SAM. All transient and dominant structures are mapped to our new alignments introduced here.

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“…The activity of small ribozymes in viroids and viroidlike RNAs seems to be also finely tuned at different steps of the replication cycle by alternative pairings in stable rodlike or branched configurations, or metastable intermediates (Di Serio et al+, 1997;Flores et al+, 1997;Matysiak et al+, 1999)+ Structural constraints due to such pairings restrict variations in viroid quasi-species, so that the majority of substitutions are located in loops (Ambros et al+, 1998) and coupled covariations are unlikely to be observed here+ On the other hand, high variability within viroid groups in most cases does not allow straightforward sequence alignments of different species+ It may be anticipated that upon accumulation of more sequence data, the analysis of covariations may help to elucidate structural rearrangements during the replication cycle of viroids and viroidlike replicons+…”

Section: Coupled Covariations and Hierarchical Foldingmentioning

confidence: 99%

Coupled nucleotide covariations reveal dynamic RNA interaction patterns

Gultyaev

Franch²,

Gerdes³

2000

RNA

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Evolutionarily conserved structures in related RNA molecules contain coordinated variations (covariations) of paired nucleotides. Analysis of covariations is a very powerful approach to deduce phylogenetically conserved (i.e., functional) conformations, including tertiary interactions. Here we discuss conserved RNA folding pathways that are revealed by covariation patterns. In such pathways, structural requirements for alternative pairings cause some nucleotides to covary with two different partners. Such "coupled" covariations between three or more nucleotides were found in various types of RNAs. The analysis of coupled covariations can unravel important features of RNA folding dynamics and improve phylogeny reconstruction in some cases. Importantly, it is necessary to distinguish between multiple covariations determined by mutually exclusive structures and those determined by tertiary contacts.

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Sequential Folding of the Genomic Ribozyme of the Hepatitis Delta Virus: Structural Analysis of RNA Transcription Intermediates

Cited by 43 publications

References 42 publications

Modeling RNA folding paths with pseudoknots: Application to hepatitis delta virus ribozyme

Modeling RNA folding paths with pseudoknots: Application to hepatitis delta virus ribozyme

Four RNA families with functional transient structures

Coupled nucleotide covariations reveal dynamic RNA interaction patterns

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