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Su, Laura F.; Chen, Liqing; Egli, Martin; Berger, James M.; Rich, Alexander

doi:10.1038/6722

Cited by 195 publications

(77 citation statements)

References 49 publications

(73 reference statements)

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“…An adenine-rich Loop B is common in vertebrate TER pseudoknots, as well as in ribosomal frameshifting viral pseudoknots (74,75). In these RNAs, the loop adenines form minor groove triples involving sugar 2′-OH and base protons (15,75). In tetPK, A90 and A91 are stacked on top of each other and pair with with C71 and C72, respectively, to form identical A•C-G triples.…”

Section: Resultsmentioning

confidence: 99%

Structure and folding of theTetrahymenatelomerase RNA pseudoknot

Cash¹,

Feigon²

2016

Nucleic Acids Res

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Telomerase maintains telomere length at the ends of linear chromosomes using an integral telomerase RNA (TER) and telomerase reverse transcriptase (TERT). An essential part of TER is the template/pseudoknot domain (t/PK) which includes the template, for adding telomeric repeats, template boundary element (TBE), and pseudoknot, enclosed in a circle by stem 1. The Tetrahymena telomerase holoenzyme catalytic core (p65-TER-TERT) was recently modeled in our 9 Å resolution cryo-electron microscopy map by fitting protein and TER domains, including a solution NMR structure of the Tetrahymena pseudoknot. Here, we describe in detail the structure and folding of the isolated pseudoknot, which forms a compact structure with major groove U•A-U and novel C•G-A+ base triples. Base substitutions that disrupt the base triples reduce telomerase activity in vitro. NMR studies also reveal that the pseudoknot does not form in the context of full-length TER in the absence of TERT, due to formation of a competing structure that sequesters pseudoknot residues. The residues around the TBE remain unpaired, potentially providing access by TERT to this high affinity binding site during an early step in TERT-TER assembly. A model for the assembly pathway of the catalytic core is proposed.

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Section: Resultsmentioning

confidence: 99%

Structure and folding of theTetrahymenatelomerase RNA pseudoknot

Cash¹,

Feigon²

2016

Nucleic Acids Res

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“…Later, a GCC + triple with a protonated cytosine was observed in a crystal structure of the frameshifting PK from the beet western yellow virus (38) and was shown to contribute to the stabilization of the PK (49). An NMR structure of the human TER PK determined by Theimer et al (21) revealed an extended triple-helical region, which includes three consecutive AUU major-groove triples in stem S2.…”

Section: Discussionmentioning

confidence: 99%

Pseudoknot structures with conserved base triples in telomerase RNAs of ciliates

Ulyanov

Shefer

James

et al. 2007

Nucleic Acids Research

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Telomerase maintains the integrity of telomeres, the ends of linear chromosomes, by adding G-rich repeats to their 3′-ends. Telomerase RNA is an integral component of telomerase. It contains a template for the synthesis of the telomeric repeats by the telomerase reverse transcriptase. Although telomerase RNAs of different organisms are very diverse in their sequences, a functional non-template element, a pseudoknot, was predicted in all of them. Pseudoknot elements in human and the budding yeast Kluyveromyces lactis telomerase RNAs contain unusual triple-helical segments with AUU base triples, which are critical for telomerase function. Such base triples in ciliates have not been previously reported. We analyzed the pseudoknot sequences in 28 ciliate species and classified them in six different groups based on the lengths of the stems and loops composing the pseudoknot. Using miniCarlo, a helical parameter-based modeling program, we calculated 3D models for a representative of each morphological group. In all cases, the predicted structure contains at least one AUU base triple in stem 2, except for that of Colpidium colpoda, which contains unconventional GCG and AUA triples. These results suggest that base triples in a pseudoknot element are a conserved feature of all telomerases.

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“…The mean RMSD for the eleven structures is 3.6 Å for our model, which out-performs 5.5 Å for the top one structure and 5.3 Å over the top five structures from the MC-Fold/MC-Sym pipeline. Especially for the pseudoknot (437d), 64 MC-Fold fails to predict the native structure as shown by the large RMSD > 10 Å . In contrast, our model gives a good prediction with RMSD = 2.7 Å for the sequence.…”

Section: Resultsmentioning

confidence: 99%

Physics-Based De Novo Prediction of RNA 3D Structures

2011

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Current experiments on structural determination cannot keep up the pace with the steadily emerging RNA sequences and new functions. This underscores the request for an accurate model for RNA three-dimensional (3D) structural prediction. Although considerable progress has been made in mechanistic studies, accurate prediction for RNA tertiary folding from sequence remains an unsolved problem. The first and most important requirement for the prediction of RNA structure from physical principles is an accurate free energy model. A recently developed three-vector virtual bond-based RNA folding model (“Vfold”) has allowed us to compute the chain entropy and predict folding free energies and structures for RNA secondary structures and simple pseudoknots. Here we develop a free energy-based method to predict larger more complex RNA tertiary folds. The approach is based on a multiscaling strategy: from the nucleotide sequence, we predict the two-dimensional (2D) structures (defined by the base pairs and tertiary contacts); based on the 2D structure, we construct a 3D scaffold; with the 3D scaffold as the initial state, we combine AMBER energy minimization and PDB-based fragment search to predict the all-atom structure. A key advantage of the approach is the statistical mechanical calculation for the conformational entropy of RNA structures, including those with cross-linked loops. Benchmark tests show that the model leads to significant improvements in RNA 3D structure prediction.

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Untitled

Cited by 195 publications

References 49 publications

Structure and folding of theTetrahymenatelomerase RNA pseudoknot

Structure and folding of theTetrahymenatelomerase RNA pseudoknot

Pseudoknot structures with conserved base triples in telomerase RNAs of ciliates

Physics-Based De Novo Prediction of RNA 3D Structures

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