Deciphering the Structure and Formation of Amyloids in Neurodegenerative Diseases With Chemical Biology Tools.
Deciphering the Structure and Formation of Amyloids in Neurodegenerative Diseases With Chemical Biology Tools.
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用化学生物学工具破译神经退行性疾病中淀粉样蛋白的结构和形成。
DOI：
10.3389/fchem.2022.886382
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发表时间：
2022
影响因子：
5.5
通讯作者：
Smet-Nocca, Caroline
中科院分区：
文献类型：
--
作者：
Landrieu, Isabelle;Dupre, Elian;Sinnaeve, Davy;El Hajjar, Lea;Smet-Nocca, Caroline
关键词：
蛋白质聚集成高度有序、有规律重复的跨 β 折叠结构（称为淀粉样原纤维），与人类疾病密切相关，例如阿尔茨海默病和帕金森病等神经退行性疾病，或 II 型糖尿病等全身性疾病。然而，在某些情况下，例如 HET-s 朊病毒，淀粉样蛋白具有生物学功能。最近，冷冻电子显微镜获得的淀粉样原纤维的高分辨率结构突显了它们的超微结构组织和多态性。然而，对于原纤维形成的分子机制和辅助因子（翻译后修饰、非蛋白质成分和其他蛋白质）的作用仍然知之甚少。淀粉样原纤维在神经退行性疾病的发病机制中是否发挥毒性或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和肽的作用模式产生新的见解，通过捕获其分子细节和构象异质性来定义其结构特征和聚集途径。这一不断扩展的领域挑战了科学家的想象力，为揭示淀粉样蛋白形成的机制细节提供了重要的工具，例如半合成蛋白质和构象变化和/或聚集的小分子传感器。用于引入蛋白质化学修饰的蛋白质工程方法和生物正交化学是应对理解淀粉样蛋白形成挑战的额外富有成果的策略。
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.
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DOI：
10.1042/bcj20200609
发表时间：
2021-07-30
期刊：
The Biochemical journal
影响因子：
--
作者：
Balana AT;Pratt MR
通讯作者：
Pratt MR
影响因子：
16.6
作者：
Ambadipudi S;Biernat J;Riedel D;Mandelkow E;Zweckstetter M
通讯作者：
Zweckstetter M
影响因子：
4.8
作者：
Babinchak, W. Michael;Haider, Raza;Surewicz, Witold K.
通讯作者：
Surewicz, Witold K.
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
影响因子：
4.8
作者：
Amniai, Laziza;Barbier, Pascale;Landrieu, Isabelle
通讯作者：
Landrieu, Isabelle