Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Amyloid / chemistry*
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Amyloid / genetics
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Amyloid / metabolism
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Amyloid / ultrastructure
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Dimerization
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Humans
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Hydrogen-Ion Concentration
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Microscopy, Electron, Transmission
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Models, Molecular*
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Mutation
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Nuclear Magnetic Resonance, Biomolecular
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Prealbumin / chemistry*
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Prealbumin / genetics
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Prealbumin / metabolism
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Protein Aggregation, Pathological / etiology
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Protein Aggregation, Pathological / genetics
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Protein Aggregation, Pathological / metabolism
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Protein Aggregation, Pathological / pathology*
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Protein Conformation
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Protein Refolding
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Protein Stability
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Protein Structure, Tertiary
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Recombinant Proteins
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Solubility
Substances
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Amyloid
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Prealbumin
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Recombinant Proteins