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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

Ball and stick model of nucleic acid.Ball and stick model of various types of nucleic acid helical forms, showing base inclination angle axis (solid red line); diameter of groove (dashed blue line).
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pone.0131788.g003: Ball and stick model of nucleic acid.Ball and stick model of various types of nucleic acid helical forms, showing base inclination angle axis (solid red line); diameter of groove (dashed blue line).

Mentions: When the refined structure of the RNA duplex was compared with a construct in which the 1x1 AA internal nucleotides were replaced with AU pairs (A-form) and a B-form DNA duplex, the inclination angles of the bases were found to be lower compared with the A-form of RNA. Such changes in the inclination of bases could be derived from stacking purine interactions [51]. Thus, a RNA duplex containing a CAG motif was found to have a conformation (A´-form) intermediate to the A- and B- forms of the nucleic acid structure (Fig 3). Such A´-forms of RNA are characterised by lower inclination angles in comparison with the A-form and a widened major groove as evident by CGG motif repeats in RNA, which causes Fragile X-syndrome [57–59]. This widening of the major groove occurs due to the presence of AA pairs, which makes it more accessible to binding proteins or small molecules. Moreover, this A´-helical form could provide unique binding sites for protein or small-molecule ligands over DNA or RNA duplexes.


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)

Ball and stick model of nucleic acid.Ball and stick model of various types of nucleic acid helical forms, showing base inclination angle axis (solid red line); diameter of groove (dashed blue line).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0131788.g003: Ball and stick model of nucleic acid.Ball and stick model of various types of nucleic acid helical forms, showing base inclination angle axis (solid red line); diameter of groove (dashed blue line).
Mentions: When the refined structure of the RNA duplex was compared with a construct in which the 1x1 AA internal nucleotides were replaced with AU pairs (A-form) and a B-form DNA duplex, the inclination angles of the bases were found to be lower compared with the A-form of RNA. Such changes in the inclination of bases could be derived from stacking purine interactions [51]. Thus, a RNA duplex containing a CAG motif was found to have a conformation (A´-form) intermediate to the A- and B- forms of the nucleic acid structure (Fig 3). Such A´-forms of RNA are characterised by lower inclination angles in comparison with the A-form and a widened major groove as evident by CGG motif repeats in RNA, which causes Fragile X-syndrome [57–59]. This widening of the major groove occurs due to the presence of AA pairs, which makes it more accessible to binding proteins or small molecules. Moreover, this A´-helical form could provide unique binding sites for protein or small-molecule ligands over DNA or RNA duplexes.

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