Structural Polymorphism of Alzheimer’s β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study
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Author(s)
Nick, Mimi
Jo, Hyunil
Lemmin, Thomas
Prusiner, Stanley B.
DeGrado, William F.
Stöhr, Jan
Elkins, Matthew Ryan
Wang, Tuo
Hong, Mei
Date Issued
August 2016
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Citation
Elkins, Matthew R. et al. “Structural Polymorphism of Alzheimer’s β-Amyloid Fibrils as Controlled by an E22 Switch: A Solid-State NMR Study.” Journal of the American Chemical Society 138, 31 (July 2016): 9840–9852 © 2016 American Chemical Society
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1021/JACS.6B03715
