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Structural dynamics of a mitochondrial tRNA possessing weak thermodynamic stability.

ABSTRACT: Folding dynamics are ubiquitously involved in controlling the multivariate functions of RNAs. While the high thermodynamic stabilities of some RNAs favor purely native states at equilibrium, it is unclear whether weakly stable RNAs exist in random, partially folded states or sample well-defined, globally folded conformations. Using a folding assay that precisely tracks the formation of native aminoacylable tRNA, we show that the folding of a weakly stable human mitochondrial (hmt) leucine tRNA is hierarchical with a distinct kinetic folding intermediate. The stabilities of the native and intermediate conformers are separated by only about 1.2 kcal/mol, and the species are readily interconvertible. Comparison of folding dynamics between unmodified and fully modified tRNAs reveals that post-transcriptional modifications produce a more constrained native structure that does not sample intermediate conformations. These structural dynamics may thus be crucial for recognition by some modifying enzymes in vivo, especially those targeting the globular core region, by allowing access to pretransition state conformers. Reduced conformational sampling of the native, modified tRNAs could then permit improved performance in downstream processes of translation. More generally, weak stabilities of small RNAs that fold in the absence of chaperone proteins may facilitate conformational switching that is central to biological function.

SUBMITTER: Bhaskaran H

PROVIDER: S-EPMC3985750 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Structural dynamics of a mitochondrial tRNA possessing weak thermodynamic stability.

Bhaskaran Hari H Taniguchi Takaaki T Suzuki Takeo T Suzuki Tsutomu T Perona John J JJ

Biochemistry 20140226 9

Folding dynamics are ubiquitously involved in controlling the multivariate functions of RNAs. While the high thermodynamic stabilities of some RNAs favor purely native states at equilibrium, it is unclear whether weakly stable RNAs exist in random, partially folded states or sample well-defined, globally folded conformations. Using a folding assay that precisely tracks the formation of native aminoacylable tRNA, we show that the folding of a weakly stable human mitochondrial (hmt) leucine tRNA i ...[more]

PMID: 24520994

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Project description:A key issue in the nucleotide excision repair (NER) of bulky carcinogen-DNA adducts is the ability of the NER machinery to recognize and repair certain adducts while failing to repair others. Unrepaired adducts can survive to cause mutations that initiate the carcinogenic process. Benzo[c]phenanthrene (B[c]Ph), a representative fjord region polycyclic aromatic hydrocarbon, can be metabolically activated to the enantiomeric benzo[c]phenanthrene diol epoxides (B[c]PhDEs), (+)-(1S,2R,3R,4S)-3,4- dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene and the corresponding (-)-(1R,2S,3S,4R) isomer. These react predominantly with adenine residues in DNA to produce the stereoisomeric 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts. Duplexes containing the 1R (+) or 1S (-) B[c]Ph-dA adduct in codon 61 of the human N-ras mutational hotspot sequence CA*A, with B[c]Ph modification at A*, are not repaired by the human NER system. However, the analogous stereoisomeric DNA adducts of the bay region benzo[a]pyrene diol epoxide (B[a]PDE), 10S (+)- and 10R (-)-trans-anti-B[a]P-N6-dA, are repaired in the same base sequence. In order to elucidate structural and thermodynamic origins of this phenomenon, we have carried out a 2 ns molecular dynamics simulation for the 1R (+)- and 1S (-)-trans-anti-B[c]Ph-N6-dA adducts in an 11mer duplex containing the human N-ras codon 61 sequence, and compared these results with our previous study of the B[a]P-dA adducts in the same sequence. The molecular mechanics Poisson- Boltzmann surface area (MM-PBSA) method was applied to calculate the free energies of the pair of stereoisomeric B[c]Ph-dA adducts, and a detailed structural analysis was carried out. The different repair susceptibilities of the B[a]P-dA adducts and the B[c]Ph-dA adducts can be attributed to different degrees of distortion, stemming from combined effects of differences in the quality of Watson-Crick hydrogen bonding, unwinding, stretching and helix backbone perturbations. These differences are due to the different intrinsic topologies of the rigid, planar bay region adducts versus the twisted, sterically hindered fjord region adducts.

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Structural dynamics of a mitochondrial tRNA possessing weak thermodynamic stability.

Publications

Structural dynamics of a mitochondrial tRNA possessing weak thermodynamic stability.

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