title: Structural Changes Associated with Transthyretin Misfolding and Amyloid Formation Revealed by Solution and Solid-State NMR.
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.
authors.affiliation: Department of Chemistry, East Carolina University , Greenville, North Carolina 27858, United States.
authors.forename: Kwang Hun
authors.initials: KH
authors.lastname: Lim
authors.affiliation: Department of Chemistry, East Carolina University , Greenville, North Carolina 27858, United States.
authors.forename: Anvesh K R
authors.initials: AK
authors.lastname: Dasari
authors.affiliation: Center of Interdisciplinary Magnetic Resonance (CIMAR), National High Magnetic Field Laboratory (NHMFL) , 1800 East Paul Dirac Drive, Tallahassee, Florida 32310, United States.
authors.forename: Ivan
authors.initials: I
authors.lastname: Hung
authors.affiliation: Center of Interdisciplinary Magnetic Resonance (CIMAR), National High Magnetic Field Laboratory (NHMFL) , 1800 East Paul Dirac Drive, Tallahassee, Florida 32310, United States.
authors.forename: Zhehong
authors.initials: Z
authors.lastname: Gan
authors.affiliation: Department of Molecular and Experimental Medicine and Skaggs Institute for Chemical Biology, The Scripps Research Institute , La Jolla, California 92037, United States.
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
authors.affiliation: Department of Chemistry, University of California , Berkeley, California 94720, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Wemmer
mesh_terms: D019943:Amino Acid Substitution; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D019281:Dimerization; D006801:Humans; D006863:Hydrogen-Ion Concentration; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011228:Prealbumin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011487:Protein Conformation; D058849:Protein Refolding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins; D012995:Solubility
chemical_list: D000682:Amyloid; D011228:Prealbumin; D011994:Recombinant Proteins