文章基本信息

标题：Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers
本地全文：下载
作者：Anvesh K. R. Dasari ; Robert M. Hughes ; Sungsool Wi 等
期刊名称：Scientific Reports
电子版ISSN：2045-2322
出版年度：2019
卷号：9
期号：1
页码：1-10
DOI：10.1038/s41598-018-37230-1
出版社：Springer Nature
摘要：Characterization of small oligomers formed at an early stage of amyloid formation is critical to understanding molecular mechanism of pathogenic aggregation process. Here we identified and characterized cytotoxic oligomeric intermediates populated during transthyretin (TTR) aggregation process. Under the amyloid-forming conditions, TTR initially forms a dimer through interactions between outer strands. The dimers are then associated to form a hexamer with a spherical shape, which serves as a building block to self-assemble into cytotoxic oligomers. Notably, wild-type (WT) TTR tends to form linear oligomers, while a TTR variant (G53A) prefers forming annular oligomers with pore-like structures. Structural analyses of the amyloidogenic intermediates using circular dichroism (CD) and solid-state NMR reveal that the dimer and oligomers have a significant degree of native-like β-sheet structures (35-38%), but with more disordered regions (~60%) than those of native TTR. The TTR variant oligomers are also less structured than WT oligomers. The partially folded nature of the oligomeric intermediates might be a common structural property of cytotoxic oligomers. The higher flexibility of the dimer and oligomers may also compensate for the entropic loss due to the oligomerization of the monomers.