Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
Exploratory Research Center on Life and Living Systems and Institute for Molecular Science, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
Molecules. 2022 Jul 26;27(15):4787. doi: 10.3390/molecules27154787.
Protein folding is the most fundamental and universal example of biomolecular self-organization and is characterized as an intramolecular process. In contrast, amyloidogenic proteins can interact with one another, leading to protein aggregation. The energy landscape of amyloid fibril formation is characterized by many minima for different competing low-energy structures and, therefore, is much more enigmatic than that of multiple folding pathways. Thus, to understand the entire energy landscape of protein aggregation, it is important to elucidate the full picture of conformational changes and polymorphisms of amyloidogenic proteins. This review provides an overview of the conformational diversity of amyloid-β (Aβ) characterized from experimental and theoretical approaches. Aβ exhibits a high degree of conformational variability upon transiently interacting with various binding molecules in an unstructured conformation in a solution, forming an α-helical intermediate conformation on the membrane and undergoing a structural transition to the β-conformation of amyloid fibrils. This review also outlines the structural polymorphism of Aβ amyloid fibrils depending on environmental factors. A comprehensive understanding of the energy landscape of amyloid formation considering various environmental factors will promote drug discovery and therapeutic strategies by controlling the fibril formation pathway and targeting the consequent morphology of aggregated structures.
蛋白质折叠是生物分子自组织最基本和最普遍的例子，其特征是一个分子内的过程。相比之下，淀粉样蛋白原性蛋白质可以相互作用，导致蛋白质聚集。淀粉样纤维形成的能量景观的特点是许多不同的竞争低能量结构的极小值，因此比多个折叠途径的能量景观更加神秘。因此，为了理解蛋白质聚集的整个能量景观，阐明淀粉样蛋白原性蛋白质的构象变化和多态性的全貌是很重要的。这篇综述概述了从实验和理论方法中表征的淀粉样蛋白-β（Aβ）的构象多样性。Aβ在溶液中以无规卷曲构象与各种结合分子短暂相互作用时表现出高度的构象可变性，在膜上形成α-螺旋中间构象，并经历结构转变为淀粉样纤维的β-构象。这篇综述还概述了 Aβ淀粉样纤维根据环境因素的结构多态性。全面了解考虑各种环境因素的淀粉样形成的能量景观将通过控制纤维形成途径和针对聚集结构的后续形态来促进药物发现和治疗策略。
