Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils

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• 作者：Michael T. Colvin ; Robert Silvers ; Qing Zhe Ni ; Thach V. Can ; Ivan Sergeyev ; Melanie Rosay ; Kevin J. Donovan ; Brian Michael ; Joseph Wall ; Sara Linse ; Robert G. Griffin
• 刊名：Journal of the American Chemical Society
• 出版年：2016
• 出版时间：August 3, 2016
• 年：2016
• 卷：138
• 期：30
• 页码：9663-9674
• 全文大小：864K
• 年卷期：0
• ISSN：1520-5126

文摘

Amyloid-β (Aβ) is a 39–42 residue protein produced by the cleavage of the amyloid precursor protein (APP), which subsequently aggregates to form cross-β amyloid fibrils that are a hallmark of Alzheimer’s disease (AD). The most prominent forms of Aβ are Aβ_1–40 and Aβ_1–42, which differ by two amino acids (I and A) at the C-terminus. However, Aβ₄₂ is more neurotoxic and essential to the etiology of AD. Here, we present an atomic resolution structure of a monomorphic form of Aβ_M01–42 amyloid fibrils derived from over 500 ¹³C–¹³C, ¹³C–¹⁵N distance and backbone angle structural constraints obtained from high field magic angle spinning NMR spectra. The structure (PDB ID: 5KK3) shows that the fibril core consists of a dimer of Aβ₄₂ molecules, each containing four β-strands in a S-shaped amyloid fold, and arranged in a manner that generates two hydrophobic cores that are capped at the end of the chain by a salt bridge. The outer surface of the monomers presents hydrophilic side chains to the solvent. The interface between the monomers of the dimer shows clear contacts between M35 of one molecule and L17 and Q15 of the second. Intermolecular ¹³C–¹⁵N constraints demonstrate that the amyloid fibrils are parallel in register. The RMSD of the backbone structure (Q15–A42) is 0.71 ± 0.12 Å and of all heavy atoms is 1.07 ± 0.08 Å. The structure provides a point of departure for the design of drugs that bind to the fibril surface and therefore interfere with secondary nucleation and for other therapeutic approaches to mitigate Aβ₄₂ aggregation.