Aubrey Liam D, Blakeman Ben J F, Lutter Liisa, Serpell Christopher J, Tuite Mick F, Serpell Louise C, Xue Wei-Feng
Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, CT2 7NJ, UK.
School of Physical Sciences, University of Kent, Canterbury, CT2 7NH, UK.
Commun Chem. 2020 Sep 11;3(1):125. doi: 10.1038/s42004-020-00372-3.
Amyloid fibrils are highly polymorphic structures formed by many different proteins. They provide biological function but also abnormally accumulate in numerous human diseases. The physicochemical principles of amyloid polymorphism are not understood due to lack of structural insights at the single-fibril level. To identify and classify different fibril polymorphs and to quantify the level of heterogeneity is essential to decipher the precise links between amyloid structures and their functional and disease associated properties such as toxicity, strains, propagation and spreading. Employing gentle, force-distance curve-based AFM, we produce detailed images, from which the 3D reconstruction of individual filaments in heterogeneous amyloid samples is achieved. Distinctive fibril polymorphs are then classified by hierarchical clustering, and sample heterogeneity is objectively quantified. These data demonstrate the polymorphic nature of fibril populations, provide important information regarding the energy landscape of amyloid self-assembly, and offer quantitative insights into the structural basis of polymorphism in amyloid populations.
淀粉样纤维是由许多不同蛋白质形成的高度多态性结构。它们具有生物学功能，但也会在众多人类疾病中异常积累。由于缺乏单纤维水平的结构见解，淀粉样多态性的物理化学原理尚不清楚。识别和分类不同的纤维多态性并量化异质性水平对于破译淀粉样结构与其功能以及与疾病相关的特性（如毒性、毒株、传播和扩散）之间的精确联系至关重要。我们采用基于力-距离曲线的温和原子力显微镜，生成详细图像，从而实现对异质淀粉样样本中单个细丝的三维重建。然后通过层次聚类对独特的纤维多态性进行分类，并客观地量化样本异质性。这些数据证明了纤维群体的多态性本质，提供了有关淀粉样自组装能量景观的重要信息，并对淀粉样群体多态性的结构基础提供了定量见解。
