Structural Polymorphism of Alzheimer's β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study.
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 singl...
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ftcdlib:oai:escholarship.org/ark:/13030/qt3sh5h1d1 2023-05-15T14:46:10+02:00 Structural Polymorphism of Alzheimer's β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study. Elkins, Matthew R Wang, Tuo Nick, Mimi Jo, Hyunil Lemmin, Thomas Prusiner, Stanley B DeGrado, William F Stöhr, Jan Hong, Mei 9840 - 9852 2016-08-01 https://escholarship.org/uc/item/3sh5h1d1 unknown eScholarship, University of California qt3sh5h1d1 https://escholarship.org/uc/item/3sh5h1d1 public Journal of the American Chemical Society, vol 138, iss 31 Humans Guanidine Thiazoles Peptides Magnetic Resonance Spectroscopy Temperature Binding Sites Protein Conformation Kinetics Phenotype Mutation Hydrogen-Ion Concentration Benzothiazoles Amyloid beta-Peptides General Chemistry Chemical Sciences article 2016 ftcdlib 2021-05-30T17:54:51Z 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. Article in Journal/Newspaper Arctic University of California: eScholarship Arctic |
institution |
Open Polar |
collection |
University of California: eScholarship |
op_collection_id |
ftcdlib |
language |
unknown |
topic |
Humans Guanidine Thiazoles Peptides Magnetic Resonance Spectroscopy Temperature Binding Sites Protein Conformation Kinetics Phenotype Mutation Hydrogen-Ion Concentration Benzothiazoles Amyloid beta-Peptides General Chemistry Chemical Sciences |
spellingShingle |
Humans Guanidine Thiazoles Peptides Magnetic Resonance Spectroscopy Temperature Binding Sites Protein Conformation Kinetics Phenotype Mutation Hydrogen-Ion Concentration Benzothiazoles Amyloid beta-Peptides General Chemistry Chemical Sciences Elkins, Matthew R Wang, Tuo Nick, Mimi Jo, Hyunil Lemmin, Thomas Prusiner, Stanley B DeGrado, William F Stöhr, Jan Hong, Mei Structural Polymorphism of Alzheimer's β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study. |
topic_facet |
Humans Guanidine Thiazoles Peptides Magnetic Resonance Spectroscopy Temperature Binding Sites Protein Conformation Kinetics Phenotype Mutation Hydrogen-Ion Concentration Benzothiazoles Amyloid beta-Peptides General Chemistry Chemical Sciences |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Elkins, Matthew R Wang, Tuo Nick, Mimi Jo, Hyunil Lemmin, Thomas Prusiner, Stanley B DeGrado, William F Stöhr, Jan Hong, Mei |
author_facet |
Elkins, Matthew R Wang, Tuo Nick, Mimi Jo, Hyunil Lemmin, Thomas Prusiner, Stanley B DeGrado, William F Stöhr, Jan Hong, Mei |
author_sort |
Elkins, Matthew R |
title |
Structural Polymorphism of Alzheimer's β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study. |
title_short |
Structural Polymorphism of Alzheimer's β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study. |
title_full |
Structural Polymorphism of Alzheimer's β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study. |
title_fullStr |
Structural Polymorphism of Alzheimer's β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study. |
title_full_unstemmed |
Structural Polymorphism of Alzheimer's β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study. |
title_sort |
structural polymorphism of alzheimer's β-amyloid fibrils as controlled by an e22 switch: a solid-state nmr study. |
publisher |
eScholarship, University of California |
publishDate |
2016 |
url |
https://escholarship.org/uc/item/3sh5h1d1 |
op_coverage |
9840 - 9852 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Journal of the American Chemical Society, vol 138, iss 31 |
op_relation |
qt3sh5h1d1 https://escholarship.org/uc/item/3sh5h1d1 |
op_rights |
public |
_version_ |
1766317421892730880 |