Institute of Protein Biochemistry, Ulm University, 89081, Ulm, Germany.
Core Unit Mass Spectrometry and Proteomics, Ulm University, 89081, Ulm, Germany.
Nat Commun. 2019 Nov 1;10(1):5008. doi: 10.1038/s41467-019-13038-z.
ATTR amyloidosis is one of the worldwide most abundant forms of systemic amyloidosis. The disease is caused by the misfolding of transthyretin protein and the formation of amyloid deposits at different sites within the body. Here, we present a 2.97 Å cryo electron microscopy structure of a fibril purified from the tissue of a patient with hereditary Val30Met ATTR amyloidosis. The fibril consists of a single protofilament that is formed from an N-terminal and a C-terminal fragment of transthyretin. Our structure provides insights into the mechanism of misfolding and implies the formation of an early fibril state from unfolded transthyretin molecules, which upon proteolysis converts into mature ATTR amyloid fibrils.
ATTR 淀粉样变性是全球最常见的系统性淀粉样变性之一。该疾病是由转甲状腺素蛋白的错误折叠和在体内不同部位形成淀粉样沉积物引起的。在这里，我们展示了从遗传性 Val30Met ATTR 淀粉样变性患者组织中纯化的纤维的 2.97 Å 冷冻电子显微镜结构。该纤维由转甲状腺素蛋白的 N 端和 C 端片段组成的单个原纤维组成。我们的结构提供了对错误折叠机制的深入了解，并暗示了未折叠转甲状腺素蛋白分子形成早期纤维状态，随后在蛋白酶解作用下转化为成熟的 ATTR 淀粉样纤维。
