Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR

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• 作者：Kwang Hun Lim ; Anvesh K. R. Dasari ; Ivan Hung ; Zhehong Gan ; Jeffery W. Kelly ; David E. Wemmer
• 刊名：Biochemistry
• 出版年：2016
• 出版时间：April 5, 2016
• 年：2016
• 卷：55
• 期：13
• 页码：1941-1944
• 全文大小：276K
• ISSN：1520-4995

文摘

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 amyloid aggregates of transthyretin using solution and solid-state nuclear magnetic resonance (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 millisecond time scales. Magic-angle-spinning solid-state NMR revealed that AB loop regions interacting with strand A in the DAGH β-sheet undergo conformational changes, leading to the destabilized DAGH β-sheet.