Landrieu Isabelle, Dupré Elian, Sinnaeve Davy, El Hajjar Léa, Smet-Nocca Caroline
University Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France.
CNRS EMR9002 Integrative Structural Biology, Lille, France.
Front Chem. 2022 May 12;10:886382. doi: 10.3389/fchem.2022.886382. eCollection 2022.
Protein aggregation into highly ordered, regularly repeated cross-β sheet structures called amyloid fibrils is closely associated to human disorders such as neurodegenerative diseases including Alzheimer's and Parkinson's diseases, or systemic diseases like type II diabetes. Yet, in some cases, such as the HET-s prion, amyloids have biological functions. High-resolution structures of amyloids fibrils from cryo-electron microscopy have very recently highlighted their ultrastructural organization and polymorphisms. However, the molecular mechanisms and the role of co-factors (posttranslational modifications, non-proteinaceous components and other proteins) acting on the fibril formation are still poorly understood. Whether amyloid fibrils play a toxic or protective role in the pathogenesis of neurodegenerative diseases remains to be elucidated. Furthermore, such aberrant protein-protein interactions challenge the search of small-molecule drugs or immunotherapy approaches targeting amyloid formation. In this review, we describe how chemical biology tools contribute to new insights on the mode of action of amyloidogenic proteins and peptides, defining their structural signature and aggregation pathways by capturing their molecular details and conformational heterogeneity. Challenging the imagination of scientists, this constantly expanding field provides crucial tools to unravel mechanistic detail of amyloid formation such as semisynthetic proteins and small-molecule sensors of conformational changes and/or aggregation. Protein engineering methods and bioorthogonal chemistry for the introduction of protein chemical modifications are additional fruitful strategies to tackle the challenge of understanding amyloid formation.
蛋白质聚集成高度有序、规则重复的交叉β片层结构（即淀粉样纤维）与人类疾病密切相关，如包括阿尔茨海默病和帕金森病在内的神经退行性疾病，或如II型糖尿病等全身性疾病。然而，在某些情况下，如HET-s朊病毒，淀粉样蛋白具有生物学功能。最近，来自冷冻电子显微镜的淀粉样纤维的高分辨率结构突出了它们的超微结构组织和多态性。然而，作用于纤维形成的分子机制以及辅助因子（翻译后修饰、非蛋白质成分和其他蛋白质）的作用仍知之甚少。淀粉样纤维在神经退行性疾病发病机制中是发挥毒性作用还是保护作用仍有待阐明。此外，这种异常的蛋白质-蛋白质相互作用对寻找针对淀粉样蛋白形成的小分子药物或免疫治疗方法提出了挑战。在这篇综述中，我们描述了化学生物学工具如何有助于对淀粉样蛋白生成蛋白和肽的作用模式有新的见解，通过捕捉它们的分子细节和构象异质性来定义它们的结构特征和聚集途径。这个不断扩展的领域挑战着科学家们的想象力，提供了关键工具来揭示淀粉样蛋白形成的机制细节，如半合成蛋白以及构象变化和/或聚集的小分子传感器。蛋白质工程方法和用于引入蛋白质化学修饰的生物正交化学是应对理解淀粉样蛋白形成挑战的额外有效策略。
