Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
Solid State Nucl Magn Reson. 2017 Nov;88:1-14. doi: 10.1016/j.ssnmr.2017.10.001. Epub 2017 Oct 4.
The aggregation of proteins and peptides into a variety of insoluble, and often non-native, aggregated states plays a central role in many devastating diseases. Analogous processes undermine the efficacy of polypeptide-based biological pharmaceuticals, but are also being leveraged in the design of biologically inspired self-assembling materials. This Trends article surveys the essential contributions made by recent solid-state NMR (ssNMR) studies to our understanding of the structural features of polypeptide aggregates, and how such findings are informing our thinking about the molecular mechanisms of misfolding and aggregation. A central focus is on disease-related amyloid fibrils and oligomers involved in neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease. SSNMR-enabled structural and dynamics-based findings are surveyed, along with a number of resulting emerging themes that appear common to different amyloidogenic proteins, such as their compact alternating short-β-strand/β-arc amyloid core architecture. Concepts, methods, future prospects and challenges are discussed.
蛋白质和肽的聚集形成了各种不溶性的、通常是非天然的聚集态，在许多破坏性疾病中起着核心作用。类似的过程削弱了基于多肽的生物药物的疗效，但也被应用于设计具有生物启发的自组装材料。本文综述了近年来固态 NMR（ssNMR）研究对我们理解多肽聚集的结构特征的重要贡献，以及这些发现如何为我们对错误折叠和聚集的分子机制的思考提供信息。本文的重点是与神经退行性疾病（如阿尔茨海默病、帕金森病和亨廷顿病）相关的淀粉样纤维和寡聚物。本文综述了基于 ssNMR 的结构和动力学研究结果，以及一些新兴的主题，这些主题似乎在不同的淀粉样蛋白中是共同的，例如它们紧凑的交替短β-折叠/β-弧形淀粉样核心结构。本文还讨论了概念、方法、未来前景和挑战。
