Low specificity of metal ion binding in the metal ion core of a folded RNA

Travers, Kevin; Boyd, Nathan; Herschlag, Daniel

doi:10.1261/rna.566007

Cited by 32 publications

(41 citation statements)

References 34 publications

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“…Specific divalent ion binding sites -if present in the folded RNA -contribute additional stability. The contributions from specifically-bound divalent cations have been isolated by saturating the ion atmosphere with monovalent cations and following the binding of two specific divalent metal ions to the core of the P4-P6 RNA [98,99] (see also [100]). …”

Section: Simple Forces Underlying the Complex Behavior Of Rnamentioning

confidence: 99%

Unwinding RNA's secrets: advances in the biology, physics, and modeling of complex RNAs

Chu

Herschlag

2008

Current Opinion in Structural Biology

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SummaryThe rapid development of our understanding of the diverse biological roles fulfilled by non-coding RNA has motivated interest in the basic macromolecular behavior, structure, and function of RNA. We focus on two areas in the behavior of complex RNAs. First, we present advances in the understanding of how RNA folding is accomplished in vivo by presenting a mechanism for the action of DEAD-box proteins. Members of this family are intimately associated with almost all cellular processes involving RNA, mediating RNA structural rearrangements and chaperoning their folding. Next, we focus on advances in understanding and characterizing the basic biophysical forces that govern the folding of complex RNAs. Ultimately we expect that a confluence and synergy between these approaches will lead to profound understanding of RNA and its biology.The explosion in our knowledge about noncoding RNA (ncRNA) -RNA that is not translated into protein -has expanded interest in RNA beyond the traditional RNA community. Diverse ncRNAs include the recently-discovered riboswitches, whose novel gene-regulation function is induced by the binding of small metabolites [1]; most of the so-called "Human Accelerated Regions" (HAR) of the human genome, whose recent evolution may be linked to the emergence of the human brain [2]; and many ncRNAs of unknown function [3]. These discoveries underscore the need to understand the fundamental macromolecular behavior of RNA, its structure and dynamics, and how these RNAs are handled and exploited in biology.Study of catalytic RNAs, which allow detection of correct folding via activity measurements, has established basic thermodynamic and kinetic properties of RNA folding. Large catalytic RNAs such as the group I intron from Tetrahymena thermophila and the RNase P RNA from Bacillus subtilis fold at vastly different rates under different conditions upon addition of Mg 2+ and have been shown to fold via multiple parallel pathways, in which different molecules follow different routes with different rates and intermediates, to a common final folded structure [4,5]. These observations support the common view that RNAs traverse rugged energy landscapes as they fold [6,7]. However, little is known about the true shape of these

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Section: Simple Forces Underlying the Complex Behavior Of Rnamentioning

confidence: 99%

Unwinding RNA's secrets: advances in the biology, physics, and modeling of complex RNAs

Chu

Herschlag

2008

Current Opinion in Structural Biology

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“…At the other end of the spectrum are specifically bound ions, which are in slow exchange and often at least partially dehydrated (Burkhardt and Zacharias 2001;van Buuren et al 2002;Draper 2004;Draper et al 2005;Stefan et al 2006). Discrimination between different ion species of the same valency (e.g., different metals from group II) is a hallmark of specific ion binding (Sosnick and Pan 2003;Draper 2004;Travers et al 2007;Lambert et al 2009). Catalytically active RNAs, such as RNase P (Guerrier-Takada et al 1986), group I introns (Grosshans and Cech 1989), the hammerhead (Dahm and Uhlenbeck 1991), hairpin (Chowrira et al 1993) and hepatitis delta virus (Nakano et al 2003) ribozymes, and the glmS ribozyme/riboswitch (Winkler et al 2004) require or are stimulated by specific divalent metal ions.…”

Section: Introductionmentioning

confidence: 99%

“…X-ray crystallography has revealed important examples of ion binding pockets (Cate and Doudna 1996;Cate et al 1997;Basu et al 1998;Conn et al 2002;Banatao et al 2003;Ennifar et al 2003;Stefan et al 2006). Complementary work using solution probes for selected RNAs has dissected aspects of specific metal ion binding and effects from the nonspecific ion atmosphere (Bukhman and Draper 1997;Horton et al 1998;DeRose 2003;Nakano et al 2003;Das et al 2005b;Travers et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Dissecting electrostatic screening, specific ion binding, and ligand binding in an energetic model for glycine riboswitch folding

Lipfert

Sim

Herschlag

et al. 2010

RNA

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Riboswitches are gene-regulating RNAs that are usually found in the 59-untranslated regions of messenger RNA. As the sugarphosphate backbone of RNA is highly negatively charged, the folding and ligand-binding interactions of riboswitches are strongly dependent on the presence of cations. Using small angle X-ray scattering (SAXS) and hydroxyl radical footprinting, we examined the cation dependence of the different folding stages of the glycine-binding riboswitch from Vibrio cholerae. We found that the partial folding of the tandem aptamer of this riboswitch in the absence of glycine is supported by all tested monoand divalent ions, suggesting that this transition is mediated by nonspecific electrostatic screening. Poisson-Boltzmann calculations using SAXS-derived low-resolution structural models allowed us to perform an energetic dissection of this process. The results showed that a model with a constant favorable contribution to folding that is opposed by an unfavorable electrostatic term that varies with ion concentration and valency provides a reasonable quantitative description of the observed folding behavior. Glycine binding, on the other hand, requires specific divalent ions binding based on the observation that Mg 2+ , Ca 2+ , and Mn 2+ facilitated glycine binding, whereas other divalent cations did not. The results provide a case study of how iondependent electrostatic relaxation, specific ion binding, and ligand binding can be coupled to shape the energetic landscape of a riboswitch and can begin to be quantitatively dissected.

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“…It has been proposed that there are two site-specific metal ion-binding sites in the P4-P6 domain of Tetrahymena group I intron ribozyme. The metal ion core of this highly structured RNA seems to bind two divalent metal ions (87,88). Moreover, P4-P6 domain has the ability to fold in high concentrations of monovalent 85)) of a group I intron.…”

Section: Modulation Of Group I Intron Activitymentioning

confidence: 99%

“…In the foreground, element P4-P6 is displayed coloured in green. ) that facilitate this folding (87). It was recently shown that for the organization of the functional architecture of the Tetrahymena group I intron active site, a number of interactions, mediated by a peripheral metal ion, are important (89).…”

Section: Modulation Of Group I Intron Activitymentioning

confidence: 99%

Insights into functional modulation of catalytic RNA activity

et al. 2008

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SummaryRNA molecules play critical roles in cell biology, and novel findings continuously broaden their functional repertoires. Apart from their well-documented participation in protein synthesis, it is now apparent that several noncoding RNAs (i.e., micro-RNAs and riboswitches) also participate in the regulation of gene expression. The discovery of catalytic RNAs had profound implications on our views concerning the evolution of life on our planet at a molecular level. A characteristic attribute of RNA, probably traced back to its ancestral origin, is the ability to interact with and be modulated by several ions and molecules of different sizes. The inhibition of ribosome activity by antibiotics has been extensively used as a therapeutical approach, while activation and substrate-specificity alteration have the potential to enhance the versatility of ribozyme-based tools in translational research. In this review, we will describe some representative examples of such modulators to illustrate the potential of catalytic RNAs as tools and targets in research and clinical approaches.

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Low specificity of metal ion binding in the metal ion core of a folded RNA

Cited by 32 publications

References 34 publications

Unwinding RNA's secrets: advances in the biology, physics, and modeling of complex RNAs

Unwinding RNA's secrets: advances in the biology, physics, and modeling of complex RNAs

Dissecting electrostatic screening, specific ion binding, and ligand binding in an energetic model for glycine riboswitch folding

Insights into functional modulation of catalytic RNA activity

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