Amyloid β 42 fibril structure based on small-angle scattering

Amyloid fibrils are associated with a number of neurodegenerative diseases, including fibrils of amyloid beta 42 peptide (A beta 42) 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 A beta 42 fibrils prepared in aqueous phosphate buffer at pH = 7.4 and pH 8.0 under quiescent conditions at 37 degrees C from pure recombinant A beta 42 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 A beta 42 fibril.

Automated summary

Amyloid fibrils, specifically A beta 42 fibrils, in neurodegenerative diseases like Alzheimer's, are toxic to neuronal cells. Small-angle scattering is used to study the dimension and shape of these fibrils, revealing an elliptical cross-section with a peptide arrangement of two filaments containing four monomers per plane. Additionally, fitting the data with a continuum model provides an atomistic model of the fibril structure.