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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

Three dimensional structure of the 1x1 nucleotide AA internal loop and its closing base pairs for RNA construct 5´ r(UUGGGCCAGCAGCAGGUCC)2.Each of the loop closing pairs has geometry consistent with that of Watson-Crick GC base pairs. The distance values (in Å) are labeled for hydrogen bonds (dashed lines); the C1´-C1´ distances (solid lines).
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pone.0131788.g002: Three dimensional structure of the 1x1 nucleotide AA internal loop and its closing base pairs for RNA construct 5´ r(UUGGGCCAGCAGCAGGUCC)2.Each of the loop closing pairs has geometry consistent with that of Watson-Crick GC base pairs. The distance values (in Å) are labeled for hydrogen bonds (dashed lines); the C1´-C1´ distances (solid lines).

Mentions: More interestingly, the 1x1 nucleotide AA internal loops show different pairing geometries (Fig 2). Two of the three 1x1 nucleotide AA internal loops have a zero hydrogen bond conformation, while the remaining loop has a single hydrogen bond conformation. In one hydrogen bond geometry, the hydrogen bond is between the hydrogen atom of the exocyclic amine (N6) of A14 and the N1 atom of A8. Zero hydrogen bond geometry has a distance greater than standard hydrogen bonds. The 1x1 nucleotide AA internal loops in the structure samples between zero and one hydrogen bond and do not disturb the loop-closing base pairs, which is evidence of their dynamic nature. Thus, this dynamic structure of the 1x1 internal AA loop supports a model for expanded CAG repeats that exhibit multiple conformations.


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)

Three dimensional structure of the 1x1 nucleotide AA internal loop and its closing base pairs for RNA construct 5´ r(UUGGGCCAGCAGCAGGUCC)2.Each of the loop closing pairs has geometry consistent with that of Watson-Crick GC base pairs. The distance values (in Å) are labeled for hydrogen bonds (dashed lines); the C1´-C1´ distances (solid lines).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131788.g002: Three dimensional structure of the 1x1 nucleotide AA internal loop and its closing base pairs for RNA construct 5´ r(UUGGGCCAGCAGCAGGUCC)2.Each of the loop closing pairs has geometry consistent with that of Watson-Crick GC base pairs. The distance values (in Å) are labeled for hydrogen bonds (dashed lines); the C1´-C1´ distances (solid lines).
Mentions: More interestingly, the 1x1 nucleotide AA internal loops show different pairing geometries (Fig 2). Two of the three 1x1 nucleotide AA internal loops have a zero hydrogen bond conformation, while the remaining loop has a single hydrogen bond conformation. In one hydrogen bond geometry, the hydrogen bond is between the hydrogen atom of the exocyclic amine (N6) of A14 and the N1 atom of A8. Zero hydrogen bond geometry has a distance greater than standard hydrogen bonds. The 1x1 nucleotide AA internal loops in the structure samples between zero and one hydrogen bond and do not disturb the loop-closing base pairs, which is evidence of their dynamic nature. Thus, this dynamic structure of the 1x1 internal AA loop supports a model for expanded CAG repeats that exhibit multiple conformations.

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