Department of Chemistry, Umeå University, SE-901 87, Umeå, Sweden.
Department of Public Health and Clinical Medicine, Umeå University, SE-901 87, Umeå, Sweden.
Nat Commun. 2021 Dec 8;12(1):7141. doi: 10.1038/s41467-021-27481-4.
Amyloid transthyretin (ATTR) amyloidosis is characterized by the abnormal accumulation of ATTR fibrils in multiple organs. However, the structure of ATTR fibrils from the eye is poorly understood. Here, we used cryo-EM to structurally characterize vitreous body ATTR fibrils. These structures were distinct from previously characterized heart fibrils, even though both have the same mutation and type A pathology. Differences were observed at several structural levels: in both the number and arrangement of protofilaments, and the conformation of the protein fibril in each layer of protofilaments. Thus, our results show that ATTR protein structure and its assembly into protofilaments in the type A fibrils can vary between patients carrying the same mutation. By analyzing and matching the interfaces between the amino acids in the ATTR fibril with those in the natively folded TTR, we are able to propose a mechanism for the structural conversion of TTR into a fibrillar form.
淀粉样转甲状腺素蛋白（ATTR）淀粉样变性的特征是 ATTR 纤维在多个器官中的异常积累。然而，眼睛中 ATTR 纤维的结构还了解甚少。在这里，我们使用 cryo-EM 对玻璃体 ATTR 纤维进行了结构表征。这些结构与先前表征的心脏纤维不同，尽管它们具有相同的突变和 A 型病理学。在几个结构水平上观察到差异：原纤维的数量和排列，以及每个原纤维层中蛋白质纤维的构象。因此，我们的结果表明，携带相同突变的患者之间，ATTR 蛋白结构及其组装成 A 型纤维中的原纤维在结构上可以有所不同。通过分析和匹配 ATTR 纤维中氨基酸与天然折叠 TTR 之间的界面，我们能够提出 TTR 向纤维形式结构转换的机制。
