School of Biosciences, Division of Natural Sciences, University of Kent, CT2 7NJ Canterbury, UK.
School of Biosciences, Division of Natural Sciences, University of Kent, CT2 7NJ Canterbury, UK.
J Mol Biol. 2021 Oct 1;433(20):167124. doi: 10.1016/j.jmb.2021.167124. Epub 2021 Jul 2.
The prediction of highly ordered three-dimensional structures of amyloid protein fibrils from the amino acid sequences of their monomeric self-assembly precursors constitutes a challenging and unresolved aspect of the classical protein folding problem. Because of the polymorphic nature of amyloid assembly whereby polypeptide chains of identical amino acid sequences under identical conditions are capable of self-assembly into a spectrum of different fibril structures, the prediction of amyloid structures from an amino acid sequence requires a detailed and holistic understanding of its assembly free energy landscape. The full extent of the structure space accessible to the cross-β molecular architecture of amyloid must also be resolved. Here, we review the current understanding of the diversity and the individuality of amyloid structures, and how the polymorphic landscape of amyloid links to biology and disease phenotypes. We present a comprehensive review of structural models of amyloid fibrils derived by cryo-EM, ssNMR and AFM to date, and discuss the challenges ahead for resolving the structural basis and the biological consequences of polymorphic amyloid assemblies.
从其单体自组装前体的氨基酸序列预测淀粉样蛋白纤维的高度有序的三维结构，是经典蛋白质折叠问题中具有挑战性和尚未解决的方面。由于淀粉样蛋白组装的多态性，相同条件下相同氨基酸序列的多肽链能够自组装成一系列不同的纤维结构，因此从氨基酸序列预测淀粉样蛋白结构需要对其组装自由能景观有详细和全面的了解。还必须解决淀粉样蛋白的交叉-β分子结构可及的结构空间的全部范围。在这里，我们回顾了对淀粉样蛋白结构的多样性和个体性的当前理解，以及淀粉样蛋白的多态性景观如何与生物学和疾病表型联系起来。我们全面回顾了迄今为止通过冷冻电镜、ssNMR 和 AFM 获得的淀粉样纤维的结构模型，并讨论了为解决多态淀粉样蛋白组装的结构基础和生物学后果而面临的挑战。
