title: Structural Polymorphism of Alzheimer's β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study.
abstract: The amyloid-β (Aβ) peptide of Alzheimer's disease (AD) forms polymorphic fibrils on the micrometer and molecular scales. Various fibril growth conditions have been identified to cause polymorphism, but the intrinsic amino acid sequence basis for this polymorphism has been unclear. Several single-site mutations in the center of the Aβ sequence cause different disease phenotypes and fibrillization properties. The E22G (Arctic) mutant is found in familial AD and forms protofibrils more rapidly than wild-type Aβ. Here, we use solid-state NMR spectroscopy to investigate the structure, dynamics, hydration and morphology of Arctic E22G Aβ40 fibrils. (13)C, (15)N-labeled synthetic E22G Aβ40 peptides are studied and compared with wild-type and Osaka E22Δ Aβ40 fibrils. Under the same fibrillization conditions, Arctic Aβ40 exhibits a high degree of polymorphism, showing at least four sets of NMR chemical shifts for various residues, while the Osaka and wild-type Aβ40 fibrils show a single or a predominant set of chemical shifts. Thus, structural polymorphism is intrinsic to the Arctic E22G Aβ40 sequence. Chemical shifts and inter-residue contacts obtained from 2D correlation spectra indicate that one of the major Arctic conformers has surprisingly high structural similarity with wild-type Aβ42. (13)C-(1)H dipolar order parameters, (1)H rotating-frame spin-lattice relaxation times and water-to-protein spin diffusion experiments reveal substantial differences in the dynamics and hydration of Arctic, Osaka and wild-type Aβ40 fibrils. Together, these results strongly suggest that electrostatic interactions in the center of the Aβ peptide sequence play a crucial role in the three-dimensional fold of the fibrils, and by inference, fibril-induced neuronal toxicity and AD pathogenesis.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Elkins
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Tuo
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco , San Francisco, California 94158, United States.
authors.forename: Mimi
authors.initials: M
authors.lastname: Nick
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco , San Francisco, California 94158, United States.
authors.forename: Hyunil
authors.initials: H
authors.lastname: Jo
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco , San Francisco, California 94158, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemmin
authors.affiliation: Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco , San Francisco, California 94158, United States.
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
authors.affiliation: Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco , San Francisco, California 94143, United States.
authors.forename: Jan
authors.initials: J
authors.lastname: Stöhr
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Mei
authors.initials: M
authors.lastname: Hong
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D052160:Benzothiazoles; D001665:Binding Sites; D019791:Guanidine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D011487:Protein Conformation; D013696:Temperature; D013844:Thiazoles / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010455:Peptides; D013844:Thiazoles; C009462:thioflavin T; D019791:Guanidine