Aggregation and Fibril Structure of AβM01–42 and Aβ1–42
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Aggregation and fibril.pdf
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Author(s)
Frederick, Kendra K.
Linse, Sara
Silvers, Robert Paul Georg
Colvin, Michael Thomas
Jacavone, Angela
Lindquist, Susan
Griffin, Robert Guy
Date Issued
August 2017
Journal
Biochemistry
Publisher
American Chemical Society (ACS)
Citation
Silvers, Robert, Michael T. Colvin, Kendra K. Frederick, Angela C. Jacavone, Susan Lindquist, Sara Linse, and Robert G. Griffin. “Aggregation and Fibril Structure of AβM01–42 and Aβ1–42.” Biochemistry 56, no. 36 (August 30, 2017): 4850–4859.
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Author's final manuscript
Abstract
A mechanistic understanding of Aβ aggregation and high-resolution structures of Aβ fibrils and oligomers are vital to elucidating relevant details of neurodegeneration in Alzheimer’s disease, which will facilitate the rational design of diagnostic and therapeutic protocols. The most detailed and reproducible insights into structure and kinetics have been achieved using Aβ peptides produced by recombinant expression, which results in an additional methionine at the N-terminus. While the length of the C-terminus is well established to have a profound impact on the peptide’s aggregation propensity, structure, and neurotoxicity, the impact of the N-terminal methionine on the aggregation pathways and structure is unclear. For this reason, we have developed a protocol to produce recombinant Aβ1–42, sans the N-terminal methionine, using an N-terminal small ubiquitin-like modifier–Aβ1–42 fusion protein in reasonable yield, with which we compared aggregation kinetics with AβM01–42 containing the additional methionine residue. The data revealed that Aβ1–42 and AβM01–42 aggregate with similar rates and by the same mechanism, in which the generation of new aggregates is dominated by secondary nucleation of monomers on the surface of fibrils. We also recorded magic angle spinning nuclear magnetic resonance spectra that demonstrated that excellent spectral resolution is maintained with both AβM01–42 and Aβ1–42 and that the chemical shifts are virtually identical in dipolar recoupling experiments that provide information about rigid residues. Collectively, these results indicate that the structure of the fibril core is unaffected by N-terminal methionine. This is consistent with the recent structures of AβM01–42 in which M0 is located at the terminus of a disordered 14-amino acid N-terminal tail.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Plasma Science and Fusion Center
Francis Bitter Magnet Laboratory (Massachusetts Institute of Technology)
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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/acs.biochem.7b00729
