Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR.
Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR.
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DOI：
10.1021/acs.biochem.6b00164
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发表时间：
2016-04-05
期刊：
影响因子：
2.9
通讯作者：
Wemmer DE
中科院分区：
文献类型：
--
作者：
Lim KH;Dasari AK;Hung I;Gan Z;Kelly JW;Wemmer DE
阐明与蛋白质错误折叠和淀粉样蛋白形成有关的结构变化对于解开淀粉样蛋白形成的分子基础至关重要。在这里，我们报告了利用溶液和固态核磁共振波谱对转甲状腺蛋白(TTR)的淀粉样变性中间体和不溶性聚集体的结构分析。我们的溶液核磁共振结果表明，两种主要β-Sheet结构中的一种(CBEFβ-Sheet)保持在具有聚集能力的中间体中，而另一种DAGHβ-Sheet在ms时间尺度上更灵活。魔角旋转固体核磁共振显示，DAGHβ-Sheet中与A链相互作用的AB环区发生构象变化，导致不稳定的DAGHβ-Sheet。
Elucidation of structural changes involved in protein misfolding and amyloid formation is crucial for unraveling the molecular basis of amyloid formation. Here we report structural analyses of the amyloidogenic intermediate and insoluble aggregates of transthyretin (TTR) using solution and solid-state NMR spectroscopy. Our solution NMR results show that one of the two main β-sheet structures (CBEF β-sheet) is maintained in the aggregation-competent intermediate, while the other DAGH β-sheet is more flexible on ms time scales. Magic-angle-spinning solid-state NMR revealed that AB loop regions interacting with strand A in DAGH β-sheet undergo conformational changes, leading to the destabilized DAGH β-sheet.