Slovenian NMR Center, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
EN-FIST Center of Excellence, Trg OF 13, SI-1000 Ljubljana, Slovenia.
Int J Mol Sci. 2023 Aug 30;24(17):13437. doi: 10.3390/ijms241713437.
The GC hexanucleotide repeat expansion in the 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 N-labeled ammonium cations as a substitute for K 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(GC) repeat, in the presence of NH ions, adopts a tetramolecular G-quadruplex with an all- quartet at the 5'-end. The movement of NH 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- quartet at the 5'-end. Furthermore, the addition of K ions to G-quadruplexes folded in the presence of NH ions induces stacking of G-quadruplexes via their 5'-end G-quartets, leading to the formation of stable higher-ordered species.
基因中的 GC 六核苷酸重复扩展是家族性肌萎缩侧索硬化症 (ALS) 和额颞叶变性 (FTLD) 的主要遗传原因，形成 G-四链体直接与这些疾病的发展有关。阳离子在 G-四链体的形成和结构中起着至关重要的作用。在这项研究中，我们研究了生物相关的钾离子对 G-四链体结构的影响，并利用 N 标记的铵阳离子作为 K 离子的替代品，以更深入地了解阳离子结合和交换动力学。通过核磁共振波谱和分子动力学模拟，我们证明在 NH 离子存在下，单个 d(GC)重复序列采用具有 5'-端全四联体的四聚体 G-四链体。NH 离子通过 G-四链体中心通道以及到体相溶液的运动受空位阳离子结合位点以及 5'-端全四联体控制。此外，向存在 NH 离子折叠的 G-四链体中添加 K 离子会通过其 5'-端 G-四联体诱导 G-四链体的堆积，从而形成稳定的高级物种。
