期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：48
DOI：10.1073/pnas.2112783118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Alzheimeŕs disease is one of the major global health challenges. Neuronal cell dysfunction and death are connected to the self-assembly of the amyloid β peptide (Aβ42) into oligomeric and fibrillar aggregates. The fibril surface can catalyze the formation of toxic oligomers via secondary nucleation. Access to a high-resolution structure of Aβ42 fibrils would provide a valuable basis for design of inhibitors of oligomer generation and toxicity in the form of fibril-binders and thus significantly contribute to the development of therapeutics against Alzheimer’s disease. A combination of methods may be most fruitful toward this aim. We show that small-angle X-ray scattering data, in combination with a solid-state NMR structure of the filament core, can reveal a detailed fibril model.
Amyloid fibrils are associated with a number of neurodegenerative diseases, including fibrils of amyloid β42 peptide (Aβ42) in Alzheimer’s disease. These fibrils are a source of toxicity to neuronal cells through surface-catalyzed generation of toxic oligomers. Detailed knowledge of the fibril structure may thus facilitate therapeutic development. We use small-angle scattering to provide information on the fibril cross-section dimension and shape for Aβ42 fibrils prepared in aqueous phosphate buffer at pH = 7.4 and pH 8.0 under quiescent conditions at 37 °C from pure recombinant Aβ42 peptide. Fitting the data using a continuum model reveals an elliptical cross-section and a peptide mass-per-unit length compatible with two filaments of two monomers, four monomers per plane. To provide a more detailed atomistic model, the data were fitted using as a starting state a high-resolution structure of the two-monomer arrangement in filaments from solid-state NMR (Protein Data Bank ID 5kk3). First, a twofold symmetric model including residues 11 to 42 of two monomers in the filament was optimized in terms of twist angle and local packing using Rosetta. A two-filament model was then built and optimized through fitting to the scattering data allowing the two N-termini in each filament to take different conformations, with the same conformation in each of the two filaments. This provides an atomistic model of the fibril with twofold rotation symmetry around the fibril axis. Intriguingly, no polydispersity as regards the number of filaments was observed in our system over separate samples, suggesting that the two-filament arrangement represents a free energy minimum for the Aβ42 fibril.
关键词：SAXS/SANS; amyloid-beta; fibril structure in solution; number of filaments; atomistic model
