Group I introns and gnra tetraloops: remnants of ‘The RNA world’?

Prathiba, J.; Malathi, R.

doi:10.1007/s11033-007-9076-4

Cited by 5 publications

(7 citation statements)

References 28 publications

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“…Consistent with this hypothesis, it has been shown that in the IC3 group I introns, 88.7% of L2 and 98.6% of the L9 peripheral tetraloops belong to the GNRA family; all of these GNRA loops are, in fact, GAAA (Prathiba and Malathi 2008). The binding affinity of a GAAA tetraloop for its 11-nt canonical receptor is up to a 1000-fold higher than the affinity of other GNRA tetraloops for the same or closely related receptor motifs (Ikawa et al 2001;Geary et al 2008).…”

Section: Less-structured Folding Intermediates Offer More Efficient Fmentioning

confidence: 67%

“…Almost all of the IA2 introns have either GUAA or GUGA as their peripheral L2 and L9 tetraloops (Prathiba and Malathi 2008), which dock into noncanonical receptors. The need to fold and splice out quickly from a cotranscriptionally translated mRNA could have disfavored the selection of tertiary interactions that potentially generate long-lived intermediates in IA2 introns.…”

Section: Less-structured Folding Intermediates Offer More Efficient Fmentioning

confidence: 99%

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RNA molecules with conserved catalytic cores but variable peripheries fold along unique energetically optimized pathways

Mitra

Laederach

Golden

et al. 2011

RNA

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Functional and kinetic constraints must be efficiently balanced during the folding process of all biopolymers. To understand how homologous RNA molecules with different global architectures fold into a common core structure we determined, under identical conditions, the folding mechanisms of three phylogenetically divergent group I intron ribozymes. These ribozymes share a conserved functional core defined by topologically equivalent tertiary motifs but differ in their primary sequence, size, and structural complexity. Time-resolved hydroxyl radical probing of the backbone solvent accessible surface and catalytic activity measurements integrated with structural-kinetic modeling reveal that each ribozyme adopts a unique strategy to attain the conserved functional fold. The folding rates are not dictated by the size or the overall structural complexity, but rather by the strength of the constituent tertiary motifs which, in turn, govern the structure, stability, and lifetime of the folding intermediates. A fundamental general principle of RNA folding emerges from this study: The dominant folding flux always proceeds through an optimally structured kinetic intermediate that has sufficient stability to act as a nucleating scaffold while retaining enough conformational freedom to avoid kinetic trapping. Our results also suggest a potential role of naturally selected peripheral A-minor interactions in balancing RNA structural stability with folding efficiency.

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Section: Less-structured Folding Intermediates Offer More Efficient Fmentioning

confidence: 67%

Section: Less-structured Folding Intermediates Offer More Efficient Fmentioning

confidence: 99%

RNA molecules with conserved catalytic cores but variable peripheries fold along unique energetically optimized pathways

Mitra

Laederach

Golden

et al. 2011

RNA

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show abstract

“…By contrast, L9/J5 folding is tightly coupled to global folding of the ribozyme, which is consistent with our prediction that isolated L9/J5 folding is substantially disfavored. The comparative instability of L9/J5 is also supported by the conservation of high affinity GAAA/11-nt-receptor sequences at L9/J5, whereas lower affinity TL/TLR sequences are often substituted at L2 and J8 ( 14 , 30 , 52 ). Together, this analysis supports that Δ G topo is a key component of the overall folding free energy of the Azoarcus ribozyme.…”

Section: Resultsmentioning

confidence: 99%

“…By contrast, TL/TLR interactions have both high Δ G topo penalties and lower topological-constraint-encoded specificities. The high thermodynamic stability and unique sequence specificity of TL/TLR motifs is thus indispensable ( 14 , 48 ), and explains the selection pressure for GAAA/11-nt-receptor sequences at L2/J8 and L9/J5 ( 30 , 52 ). Our results also point to a role for negative design, as the non-GNRA sequences of loops L6 and L8 likely help negate the otherwise low Δ G topo of forming non-native contacts with J2 and J5.…”

Section: Discussionmentioning

confidence: 99%

Secondary structure encodes a cooperative tertiary folding funnel in theAzoarcusribozyme

2015

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A requirement for specific RNA folding is that the free-energy landscape discriminate against non-native folds. While tertiary interactions are critical for stabilizing the native fold, they are relatively non-specific, suggesting additional mechanisms contribute to tertiary folding specificity. In this study, we use coarse-grained molecular dynamics simulations to explore how secondary structure shapes the tertiary free-energy landscape of the Azoarcus ribozyme. We show that steric and connectivity constraints posed by secondary structure strongly limit the accessible conformational space of the ribozyme, and that these so-called topological constraints in turn pose strong free-energy penalties on forming different tertiary contacts. Notably, native A-minor and base-triple interactions form with low conformational free energy, while non-native tetraloop/tetraloop–receptor interactions are penalized by high conformational free energies. Topological constraints also give rise to strong cooperativity between distal tertiary interactions, quantitatively matching prior experimental measurements. The specificity of the folding landscape is further enhanced as tertiary contacts place additional constraints on the conformational space, progressively funneling the molecule to the native state. These results indicate that secondary structure assists the ribozyme in navigating the otherwise rugged tertiary folding landscape, and further emphasize topological constraints as a key force in RNA folding.

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“…5D). These conserved hexaloops may be stabilized by internal interactions similar to the G-A pairing and R stacking of GNRA tetraloops and some related pentaloops involved in other RNA-protein interactions (10,21,43,59). Such non-Watson-Crick interactions might explain why, as revealed by structure probing, a predicted A-U pair at the top of the stem-loop 90 stem does not form, preserving the hexaloop conformation of the related loops in other nodaviruses (Fig.…”

Section: Discussionmentioning

confidence: 99%

5′ cis Elements Direct Nodavirus RNA1 Recruitment to Mitochondrial Sites of Replication Complex Formation

Wynsberghe

Ahlquist

2009

J Virol

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Positive-strand RNA viruses replicate their genomes on intracellular membranes, usually in conjunction with virus-induced membrane rearrangements. For the nodavirus flock house virus (FHV), we recently showed that multifunctional FHV replicase protein A induces viral RNA template recruitment to a membraneassociated state, but the site(s) and function of this recruitment were not determined. By tagging viral RNA with green fluorescent protein, we show here in Drosophila cells that protein A recruits FHV RNA specifically to the outer mitochondrial membrane sites of RNA replication complex formation. Using Drosophila cells and yeast cells, which also support FHV replication, we also defined the cis-acting regions that direct replication and template recruitment for FHV genomic RNA1. RNA1 nucleotides 68 to 205 were required for RNA replication and directed efficient protein A-mediated RNA recruitment in both cell types. RNA secondary structure prediction, structure probing, and phylogenetic comparisons in this region identified two stable, conserved stem-loops with nearly identical loop sequences. Further mutational analysis showed that both stem-loops and certain flanking sequences were required for RNA1 recruitment, negative-strand synthesis, and subsequent positive-strand amplification in yeast and Drosophila cells. Thus, we have shown that protein A recruits RNA1 templates to mitochondria, as expected for RNA replication, and identified a new RNA1 cis element that is necessary and sufficient for RNA1 template recognition and recruitment to these mitochondrial membranes for negative-strand RNA1 synthesis. These results establish RNA recruitment to the sites of replication complex formation as an essential, distinct, and selective early step in nodavirus replication.All positive-strand RNA viruses replicate their genomes in virus-induced replication complexes associated with rearranged intracellular membranes (50). Different viruses replicate in association with different intracellular membranes, with endoplasmic reticulum-derived membranes used most frequently (50). Replication complexes may serve many purposes, including localizing all required viral and cellular factors in close proximity and high concentration to allow effective initiation and efficient progression of replication, protecting replication intermediates such as double-stranded RNA from antiviral responses, and providing a scaffold to organize sequential replication steps (50). Although these complexes are crucial for positive-strand RNA virus replication, their formation is not well understood.For replication complexes to form and function, viral replication proteins, viral genomic RNA, and any required host factors must localize to the relevant intracellular membranes where replication complexes assemble. Some viral replication proteins such as hepatitis C virus (HCV) NS4B, brome mosaic virus (BMV) protein 1a, and tombusvirus p33 direct their own localization to the appropriate membrane (14,49,53). Other viral replication proteins are directed t...

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Group I introns and gnra tetraloops: remnants of ‘The RNA world’?

Cited by 5 publications

References 28 publications

RNA molecules with conserved catalytic cores but variable peripheries fold along unique energetically optimized pathways

RNA molecules with conserved catalytic cores but variable peripheries fold along unique energetically optimized pathways

Secondary structure encodes a cooperative tertiary folding funnel in theAzoarcusribozyme

5′ cis Elements Direct Nodavirus RNA1 Recruitment to Mitochondrial Sites of Replication Complex Formation

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