Multistep Changes in Amyloid Structure Induced by Cross-Seeding on a Rugged Energy Landscape.
Multistep Changes in Amyloid Structure Induced by Cross-Seeding on a Rugged Energy Landscape.
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在崎岖的能源景观上交叉播种引起的淀粉样蛋白结构的多步变化。
DOI：
10.1016/j.bpj.2020.12.005
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发表时间：
2020
期刊：
影响因子：
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通讯作者：
Keisuke Yuzu,Naoki Yamamoto,Masahiro Noji,Masatomo So,Yuji Goto,Tetsushi Iwasaki,Motonari Tsubaki,Eri Chatani
中科院分区：
文献类型：
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作者：
高橋美貴;長田和樹;綿貫優実;山口昌樹;八代拓也;八須匡和;西山千春;Keisuke Yuzu,Naoki Yamamoto,Masahiro Noji,Masatomo So,Yuji Goto,Tetsushi Iwasaki,Motonari Tsubaki,Eri Chatani
淀粉样原纤维是与各种淀粉样变性和神经退行性疾病相关的异常蛋白质聚集体。近年来研究表明，淀粉样纤维的结构多样性往往导致不同的病理表型，包括细胞毒性和感染性。不同的结构被预测通过种子依赖性生长来传播，这是淀粉样纤维的特征性质之一。然而，关于淀粉样蛋白结构到底如何通过接种反应遗传给后代，还有很多未知之处。在这里，我们调查的行为自我和交叉播种的淀粉样纤维的人和牛胰岛素的硫磺素T荧光，形态，二级结构，碘染色。胰岛素淀粉样纤维表现出不同的结构，这取决于物种，其中每一个复制自我播种。相反，在交叉接种中观察到逐渐的结构变化，当人胰岛素与牛胰岛素种子接种时，形成了具有独特形态和细胞毒性的新型淀粉样结构。值得注意的是，碘染色跟踪淀粉样蛋白结构的变化灵敏，奇异值分解分析的紫外可见吸收光谱的纤维结合碘揭示了存在一个或多个中间亚稳态的结构变化过程中。从这些发现中，我们提出了一个传播计划与两个异源蛋白，这是占作为一个结果的崎岖的能量景观的淀粉样蛋白形成之间的交叉播种的多步结构变化。
Amyloid fibrils are aberrant protein aggregates associated with various amyloidoses and neurodegenerative diseases. It is recently indicated that structural diversity of amyloid fibrils often results in different pathological phenotypes, including cytotoxicity and infectivity. The diverse structures are predicted to propagate by seed-dependent growth, which is one of the characteristic properties of amyloid fibrils. However, much remains unknown regarding how exactly the amyloid structures are inherited to subsequent generations by seeding reaction. Here, we investigated the behaviors of self- and cross-seeding of amyloid fibrils of human and bovine insulin in terms of thioflavin T fluorescence, morphology, secondary structure, and iodine staining. Insulin amyloid fibrils exhibited different structures, depending on species, each of which replicated in self-seeding. In contrast, gradual structural changes were observed in cross-seeding, and a new type of amyloid structure with distinct morphology and cytotoxicity was formed when human insulin was seeded with bovine insulin seeds. Remarkably, iodine staining tracked changes in amyloid structure sensitively, and singular value decomposition analysis of the ultraviolet-visible absorption spectra of the fibril-bound iodine has revealed the presence of one or more intermediate metastable states during the structural changes. From these findings, we propose a propagation scheme with multistep structural changes in cross-seeding between two heterologous proteins, which is accounted for as a consequence of the rugged energy landscape of amyloid formation.