Aggregation and the Intrinsic Structural Disorder of Dipeptide Repeat Peptides of C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Characterized by NMR.
Aggregation and the Intrinsic Structural Disorder of Dipeptide Repeat Peptides of C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Characterized by NMR.
复制标题
NMR 表征的 C9orf72 相关肌萎缩侧索硬化症和额颞叶痴呆的二肽重复肽的聚集和内在结构紊乱。
DOI：
10.1021/acs.jpcb.1c08149
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Ramamoorthy,Ayyalusamy
中科院分区：
文献类型：
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作者：
Krishnarjuna,Bankala;Ivanova,MagdalenaI;Ramamoorthy,Ayyalusamy
已知二肽重复序列 (DPR) 在 C9ORF72 相关的肌萎缩侧索硬化症 (ALS) 和额颞叶痴呆 (FTD) 中发挥重要作用。对 DPR 的研究报告了这些肽聚集体的聚集动力学、毒性和低分辨率形态。虽然 Gly-Pro [(GP)6] 的二肽六重复序列已被证明是非聚集的，但 Gly-Ala [(GA)6] 和 Gly-Arg [(GR)6] 表现出神经毒性聚集物的形成。然而，这些 DPR 的结构研究一直难以捉摸。在这项研究中，我们探索了通过核磁共振实验对溶液中这些肽的实时聚集进行高分辨率监测的可行性。尽管(GP)6是无序且非聚集的，但从NMR谱中观察到顺式和反式构象的存在。值得注意的是，(GR)6 表现出多种构象的形成，而疏水性和低溶解度的 (GA)6 以温度依赖性方式快速聚集。这些结果证明了通过溶液核磁共振实验监测高度无序肽、聚集动力学和小分子量聚集体形成的微小构象变化的可行性。检测 (GP)6 中顺式和反式异构化的能力值得注意，对于通过 NMR 研究本质上无序的蛋白质/肽可能很有价值。早期检测微小的构象变化对于更好地理解有毒中间体形成的机制和开发抑制它们的方法具有重要意义，并有可能有助于开发治疗毁灭性的 C9ORF72 相关 ALS 和 FTD 疾病的化合物。
Dipeptide repeats (DPRs) are known to play important roles in C9ORF72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies on DPRs have reported on the kinetics of aggregation, toxicity, and low-resolution morphology of the aggregates of these peptides. While the dipeptide hexa-repeats of Gly-Pro [(GP)6] have been shown to be nonaggregating, Gly-Ala [(GA)6] and Gly-Arg [(GR)6] exhibited the formation of neurotoxic aggregates. However, structural studies of these DPRs have been elusive. In this study, we explored the feasibility of a high-resolution monitoring of a real-time aggregation of these peptides in a solution by using NMR experiments. Although (GP)6is disordered and nonaggregating, the existence ofcisandtransconformations was observed from NMR spectra. It was remarkable that the (GR)6exhibited the formation of multiple conformations, whereas the hydrophobic and low-soluble (GA)6aggregated fast in a temperature-dependent manner. These results demonstrate the feasibility of monitoring the minor conformational changes from highly disordered peptides, aggregation kinetics, and the formation of small molecular weight aggregates by solution NMR experiments. The ability to detectcisandtranslocal isomerizations in (GP)6is noteworthy and could be valuable to study intrinsically disordered proteins/peptides by NMR. The early detection of minor conformational changes could be valuable in better understanding the mechanistic insights into the formation of toxic intermediates and the development of approaches to inhibit them and, potentially, aid in the development of compounds to treat the devastating C9ORF72-related ALS and FTD diseases.