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Structural Insights Reveal the Dynamics of the Repeating r(CAG) Transcript Found in Huntington's Disease (HD) and Spinocerebellar Ataxias (SCAs).

Tawani A, Kumar A - PLoS ONE (2015)

Bottom Line: Moreover, mutant huntingtin protein translated from expanded r(CAG) also yields toxic effects.The overall RNA structure has helical parameters intermediate to the A- and B-forms of nucleic acids due to the global widening of major grooves and base-pair preferences near internal AA loops.The comprehension of structural behaviour by studying the spectral features and the dynamics also supports the flexible nature of the r(CAG) motif.

View Article: PubMed Central - PubMed

Affiliation: Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, India.

ABSTRACT
In humans, neurodegenerative disorders such as Huntington's disease (HD) and many spinocerebellar ataxias (SCAs) have been found to be associated with CAG trinucleotide repeat expansion. An important RNA-mediated mechanism that causes these diseases involves the binding of the splicing regulator protein MBNL1 (Muscleblind-like 1 protein) to expanded r(CAG) repeats. Moreover, mutant huntingtin protein translated from expanded r(CAG) also yields toxic effects. To discern the role of mutant RNA in these diseases, it is essential to gather information about its structure. Detailed insight into the different structures and conformations adopted by these mutant transcripts is vital for developing therapeutics targeting them. Here, we report the crystal structure of an RNA model with a r(CAG) motif, which is complemented by an NMR-based solution structure obtained from restrained Molecular Dynamics (rMD) simulation studies. Crystal structure data of the RNA model resolved at 2.3 Å reveals non-canonical pairing of adenine in 5´-CAG/3´-GAC motif samples in different syn and anti conformations. The overall RNA structure has helical parameters intermediate to the A- and B-forms of nucleic acids due to the global widening of major grooves and base-pair preferences near internal AA loops. The comprehension of structural behaviour by studying the spectral features and the dynamics also supports the flexible nature of the r(CAG) motif.

No MeSH data available.


Related in: MedlinePlus

Lowest energy conformation of 5´ r(CCGCAGCGG)2.A. The lowest energy conformation of CAG motif obtained after rMD simulation of 5´ r(CCGCAGCGG)2. B. Ensemble of ten lowest energy structures of 5´ r(CCGCAGCGG)2 obtained after rMD simulation. C. Ensemble of ten lowest energy structures of AA pairs of 5´ r(CCGCAGCGG)2 obtained after rMD simulation.
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pone.0131788.g007: Lowest energy conformation of 5´ r(CCGCAGCGG)2.A. The lowest energy conformation of CAG motif obtained after rMD simulation of 5´ r(CCGCAGCGG)2. B. Ensemble of ten lowest energy structures of 5´ r(CCGCAGCGG)2 obtained after rMD simulation. C. Ensemble of ten lowest energy structures of AA pairs of 5´ r(CCGCAGCGG)2 obtained after rMD simulation.

Mentions: Analysis of the AA pair geometry showed the existence of zero and one hydrogen bonds in the simulation trajectory, which is analogous to the crystal structure. The lowest energy conformation observed after simulation showed a single hydrogen bond between the non-canonical adenine pair (Fig 7A). In contrast with the AA pair, the loop closing GC pairs had a geometry consistent with that of Watson-Crick GC base pairing (Fig 7A). Furthermore, the C1´-C1´ distances between the adenine pair and loop-closing GC pairs were in line with the crystal data, thus supporting the model for an A´- form of RNA [57] (Fig 7A).


Structural Insights Reveal the Dynamics of the Repeating r(CAG) Transcript Found in Huntington's Disease (HD) and Spinocerebellar Ataxias (SCAs).

Tawani A, Kumar A - PLoS ONE (2015)

Lowest energy conformation of 5´ r(CCGCAGCGG)2.A. The lowest energy conformation of CAG motif obtained after rMD simulation of 5´ r(CCGCAGCGG)2. B. Ensemble of ten lowest energy structures of 5´ r(CCGCAGCGG)2 obtained after rMD simulation. C. Ensemble of ten lowest energy structures of AA pairs of 5´ r(CCGCAGCGG)2 obtained after rMD simulation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493008&req=5

pone.0131788.g007: Lowest energy conformation of 5´ r(CCGCAGCGG)2.A. The lowest energy conformation of CAG motif obtained after rMD simulation of 5´ r(CCGCAGCGG)2. B. Ensemble of ten lowest energy structures of 5´ r(CCGCAGCGG)2 obtained after rMD simulation. C. Ensemble of ten lowest energy structures of AA pairs of 5´ r(CCGCAGCGG)2 obtained after rMD simulation.
Mentions: Analysis of the AA pair geometry showed the existence of zero and one hydrogen bonds in the simulation trajectory, which is analogous to the crystal structure. The lowest energy conformation observed after simulation showed a single hydrogen bond between the non-canonical adenine pair (Fig 7A). In contrast with the AA pair, the loop closing GC pairs had a geometry consistent with that of Watson-Crick GC base pairing (Fig 7A). Furthermore, the C1´-C1´ distances between the adenine pair and loop-closing GC pairs were in line with the crystal data, thus supporting the model for an A´- form of RNA [57] (Fig 7A).

Bottom Line: Moreover, mutant huntingtin protein translated from expanded r(CAG) also yields toxic effects.The overall RNA structure has helical parameters intermediate to the A- and B-forms of nucleic acids due to the global widening of major grooves and base-pair preferences near internal AA loops.The comprehension of structural behaviour by studying the spectral features and the dynamics also supports the flexible nature of the r(CAG) motif.

View Article: PubMed Central - PubMed

Affiliation: Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, India.

ABSTRACT
In humans, neurodegenerative disorders such as Huntington's disease (HD) and many spinocerebellar ataxias (SCAs) have been found to be associated with CAG trinucleotide repeat expansion. An important RNA-mediated mechanism that causes these diseases involves the binding of the splicing regulator protein MBNL1 (Muscleblind-like 1 protein) to expanded r(CAG) repeats. Moreover, mutant huntingtin protein translated from expanded r(CAG) also yields toxic effects. To discern the role of mutant RNA in these diseases, it is essential to gather information about its structure. Detailed insight into the different structures and conformations adopted by these mutant transcripts is vital for developing therapeutics targeting them. Here, we report the crystal structure of an RNA model with a r(CAG) motif, which is complemented by an NMR-based solution structure obtained from restrained Molecular Dynamics (rMD) simulation studies. Crystal structure data of the RNA model resolved at 2.3 Å reveals non-canonical pairing of adenine in 5´-CAG/3´-GAC motif samples in different syn and anti conformations. The overall RNA structure has helical parameters intermediate to the A- and B-forms of nucleic acids due to the global widening of major grooves and base-pair preferences near internal AA loops. The comprehension of structural behaviour by studying the spectral features and the dynamics also supports the flexible nature of the r(CAG) motif.

No MeSH data available.


Related in: MedlinePlus