Insight into Tetramolecular DNA G-Quadruplexes Associated with ALS and FTLD: Cation Interactions and Formation of Higher-Ordered Structure
The G<sub>4</sub>C<sub>2</sub> hexanucleotide repeat expansion in the <i>c9orf72</i> gene is a major genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), with the formation of G-quadruplexes directly linked to...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/17/13437 |
| Summary: | The G<sub>4</sub>C<sub>2</sub> hexanucleotide repeat expansion in the <i>c9orf72</i> gene is a major genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), with the formation of G-quadruplexes directly linked to the development of these diseases. Cations play a crucial role in the formation and structure of G-quadruplexes. In this study, we investigated the impact of biologically relevant potassium ions on G-quadruplex structures and utilized <sup>15</sup>N-labeled ammonium cations as a substitute for K<sup>+</sup> ions to gain further insights into cation binding and exchange dynamics. Through nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we demonstrate that the single d(G<sub>4</sub>C<sub>2</sub>) repeat, in the presence of <sup>15</sup>NH<sub>4</sub><sup>+</sup> ions, adopts a tetramolecular G-quadruplex with an all-<i>syn</i> quartet at the 5′-end. The movement of <sup>15</sup>NH<sub>4</sub><sup>+</sup> ions through the central channel of the G-quadruplex, as well as to the bulk solution, is governed by the vacant cation binding site, in addition to the all-<i>syn</i> quartet at the 5′-end. Furthermore, the addition of K<sup>+</sup> ions to G-quadruplexes folded in the presence of <sup>15</sup>NH<sub>4</sub><sup>+</sup> ions induces stacking of G-quadruplexes via their 5′-end G-quartets, leading to the formation of stable higher-ordered species. |
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| ISSN: | 1661-6596 1422-0067 |