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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

Comparison of the electrostatic charge distributions for CAG structure to duplex RNA and DNA.Panels A-D are electrostatic charge distributions; A. CAG structure; B. CGG structure (PDB 3SJ2); C. CUG structure (PDB 3SZX) and; D., E. a structure in which the 1x1 nucleotide AA internal loops in the CAG construct were replaced with GC pairs and AU pairs, respectively.
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pone.0131788.g004: Comparison of the electrostatic charge distributions for CAG structure to duplex RNA and DNA.Panels A-D are electrostatic charge distributions; A. CAG structure; B. CGG structure (PDB 3SJ2); C. CUG structure (PDB 3SZX) and; D., E. a structure in which the 1x1 nucleotide AA internal loops in the CAG construct were replaced with GC pairs and AU pairs, respectively.

Mentions: Furthermore, this refined structure also yields interesting features about the electrostatic differences between canonically paired RNA duplexes and r(CAG) repeat RNAs. The electrostatic distribution shows that these repeats have a larger density of partial positive charges in the minor groove (Fig 4A–4E), which may be exploited for the binding of small molecules.


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)

Comparison of the electrostatic charge distributions for CAG structure to duplex RNA and DNA.Panels A-D are electrostatic charge distributions; A. CAG structure; B. CGG structure (PDB 3SJ2); C. CUG structure (PDB 3SZX) and; D., E. a structure in which the 1x1 nucleotide AA internal loops in the CAG construct were replaced with GC pairs and AU pairs, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131788.g004: Comparison of the electrostatic charge distributions for CAG structure to duplex RNA and DNA.Panels A-D are electrostatic charge distributions; A. CAG structure; B. CGG structure (PDB 3SJ2); C. CUG structure (PDB 3SZX) and; D., E. a structure in which the 1x1 nucleotide AA internal loops in the CAG construct were replaced with GC pairs and AU pairs, respectively.
Mentions: Furthermore, this refined structure also yields interesting features about the electrostatic differences between canonically paired RNA duplexes and r(CAG) repeat RNAs. The electrostatic distribution shows that these repeats have a larger density of partial positive charges in the minor groove (Fig 4A–4E), which may be exploited for the binding of small molecules.

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