Folding of RNA involves parallel pathways

Pan, Jie; Thirumalai, D.; Woodson, Sarah A.

doi:10.1006/jmbi.1997.1311

Cited by 193 publications

(243 citation statements)

References 36 publications

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“…When C > C m , the midpoint of the transition from U to the N, RNA becomes compact as a result of formation of tertiary contacts. For many RNA molecules, such as the Tetrahymena ribozyme and RNase P, folding to the native state is preceded by the formation of multiple metastable kinetic intermediates (I) [1,2,7].The large dynamic conformational fluctuations in the U and I states make it difficult to characterize their structures. However, small angle scattering experiments can be used to determine the shape of RNA as it folds.…”

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Persistence Length Changes Dramatically as RNA Folds

et al. 2005

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We determine the persistence length, lp, for a bacterial group I ribozyme as a function of concentration of monovalent and divalent cations by fitting the distance distribution functions P (r) obtained from small angle X-ray scattering intensity data to the asymptotic form of the calculated PW LC (r) for a worm-like chain (WLC). The lp values change dramatically over a narrow range of Mg 2+ concentration from ∼21Å in the unfolded state (U) to ∼10Å in the compact (IC) and native states. Variations in lp with increasing Na + concentration are more gradual. In accord with the predictions of polyelectrolyte theory we find lp ∝ 1/κ 2 where κ is the inverse Debye-screening length.Elucidating the mechanisms by which RNA molecules self-assemble to form three dimensional structures is a challenging problem [1,2,3,4]. Because the native state (N) cannot form without significantly neutralizing the negative charge on [5,6] the phosphate group, RNA folding is sensitive to the valence, size, and shape of the counterions. At low counterion concentrations (C) RNA is unfolded (U) in the sense that it contains isolated stretches of base-paired stem loops that have large dynamical fluctuations. When C > C m , the midpoint of the transition from U to the N, RNA becomes compact as a result of formation of tertiary contacts. For many RNA molecules, such as the Tetrahymena ribozyme and RNase P, folding to the native state is preceded by the formation of multiple metastable kinetic intermediates (I) [1,2,7].The large dynamic conformational fluctuations in the U and I states make it difficult to characterize their structures. However, small angle scattering experiments can be used to determine the shape of RNA as it folds. The conformation of RNA in the U, N, and the I states is characterized by R g , the radius of gyration, and l p , the persistence length. Small Angle X-ray Scattering (SAXS) [2,8,9,10,11] and Small Angle Neutron Scattering (SANS) [12] experiments have been used to obtain R g as a function of counterions for a number of RNA molecules. In contrast, l p , which is a function of C and valence and shape of counterions, is more difficult to obtain.In this letter, we use SAXS data and theoretical results for the worm-like chain (WLC) to obtain l p for a 195 nucleotide group I ribozyme from pre-tRNA(Ile) of the Azoarcus bacterium as a function of C for monovalent and divalent counterions. The major conclusions of the present study are: (i) The experimentally determined distance distribution functions P (r) can be accurately fit using the theoretical results for wormlike chains for r/R g > 1 where R g is the radius of gyration of RNA. The l p values, which were calculated by fitting P (r) to P W LC (r) for r > R g , change dramatically from l p ≃ 21Å in the U state to l p ≃ 10 A in the compact conformation. (ii) The large reduction in l p occurs abruptly over a narrow concentration range in Mg 2+ whereas the decrease of l p in Na + is gradual. This result suggests that the compaction of RNA resembles a first order transition i...

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Persistence Length Changes Dramatically as RNA Folds

et al. 2005

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“…[48,[104][105][106] For instance, riboswitches usually perform their functions by changing structure rather than retaining a static native structure. [106] This indicates that the kinetic RNA structures that developed during the folding process can be important for RNA functions.…”

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RNA structure prediction: Progress and perspective

Shi¹,

Wu²,

Wang³

et al. 2014

Chinese Phys. B

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Many recent exciting discoveries have revealed the versatility of RNAs and their impo rtance in a variety of cellular functions which are strongly coupled to RNA structures. To understand the functions of RNAs, some structure prediction models have been developed in recent years. In this review, the progress in computational models for RNA structure prediction is introduced and the distinguishing features of many outstanding algorithms are discussed, emphasizing three dimensional (3D) structure prediction. A promising coarse-grained model for predicting RNA 3D structure, stability and salt effect is also introduced briefly. Finally, we discuss the major challenges in the RNA 3D structure modeling.

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“…In vitro, RNA molecules partition among competing folding pathways, which lead either to the native or misfolded structures (Thirumalai and Woodson 1996). A number of experiments have shown that the Tetrahymena ribozyme folds through multiple pathways (Pan et al 1997(Pan et al , 2000Zhuang et al 2000;Laederach et al 2006). In vitro, kinetic partitioning may occur early in the folding process, perhaps when the secondary structure is formed.…”

Section: Rna Partitioning In Vivomentioning

confidence: 99%

Self-splicing of a group I intron reveals partitioning of native and misfolded RNA populations in yeast

Jackson¹,

Koduvayur²,

Woodson³

2006

RNA

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Stable RNAs must form specific three-dimensional structures, yet many RNAs become kinetically trapped in misfolded conformations. To understand the factors that control the accuracy of RNA folding in the cell, the self-splicing activity of the Tetrahymena group I intron was compared in different genetic contexts in budding yeast. The extent of splicing was 98% when the intron was placed in its natural rDNA context, but only 3% when the intron was expressed in an exogenous pre-mRNA. Further experiments showed that the probability of forming the active intron structure depends on local sequence context and transcription by Pol I. Pre-rRNAs decayed at similar rates, whether the intron was wild type or inactivated by an internal deletion, suggesting that most of the unreacted pre-rRNA is incompetent to splice. Northern blots and complementation assays showed that mutations that destabilize the intron tertiary structure inhibited self-splicing and processing of internal transcribed spacer 2. The data are consistent with partitioning of pre-rRNAs into active and inactive populations. The misfolded RNAs are sequestered and degraded without refolding to a significant extent. Thus, the initial fidelity of folding can dictate the intracellular fate of transcripts containing this group I intron.

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Folding of RNA involves parallel pathways

Cited by 193 publications

References 36 publications

Persistence Length Changes Dramatically as RNA Folds

Persistence Length Changes Dramatically as RNA Folds

RNA structure prediction: Progress and perspective

Self-splicing of a group I intron reveals partitioning of native and misfolded RNA populations in yeast

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