RT Journal Article
SR Electronic
T1 Structural Model for Self-Limiting β-strand Arrangement Within an Alzheimer’s Amyloid-β Oligomer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.12.06.519347
DO 10.1101/2022.12.06.519347
A1 Gao, Yuan
A1 Prasad, Ramesh
A1 Randolph, Peter S.
A1 Watzlawik, Jens O.
A1 Robang, Alicia S.
A1 Guo, Cong
A1 Stagg, Scott M.
A1 Zhou, Huan-Xiang
A1 Rosenberry, Terrone L.
A1 Paravastu, Anant K.
YR 2022
UL http://biorxiv.org/content/early/2022/12/06/2022.12.06.519347.abstract
AB Previous reports revealed that sodium dodecyl sulfate near its critical micelle concentration can drive the assembly of Aβ42 along an oligomeric pathway. This pathway produces a 150 kDa peptide oligomer (approximately 32 peptide molecules or protomers) that does not aggregate further into amyloid fibrils. Solid-state nuclear magnetic resonance (NMR) spectroscopy revealed structural features distinguishing the 150 kDa oligomer from fibrils. A puzzling feature was the coexistence of parallel and antiparallel β-sheets within the oligomer structure. Here we present new atomic-level structural constraints obtained via solid-state NMR spectroscopy, benefitting from improved resolution via sample concentration by ultracentrifugation. In addition, two-dimensional cryo-electron microscopy (cryo-EM) reconstruction revealed a 4-fold symmetric shape. We propose a structural model to rationalize the solid-sate NMR- and cryo-EM-derived structural constraints. This model has a hollow square cylinder shape, with antiparallel β-sheets formed by residues 33-39 lining the inner walls and parallel β-sheets formed by residues 11-22 lining the outer walls. Within successive layers, the outer β-strands on each side of the square cylinder alternate between two forms: one within a U-shaped protomer and another within L-shaped protomer. Molecular dynamics simulations show that, when the oligomer model is embedded in a lipid membrane, ions permeate through the central pore, with cation selectivity. The model further motivates an assembly pathway-based interpretation that may explain why the 150 kDa oligomer does not undergo further aggregation into amyloid fibrils.Significance Statement Aβ oligomers are thought to be the most toxic species in Alzheimer’s disease. Their sizes range from 2 to ∼50 protomers. Most published experimental data on Aβ oligomers indicate that they, like fibrils, are composed of β-sheets, but it is a mystery why any β-sheet aggregate would exist as a stable oligomer without undergoing further aggregation into fibrils. Here, structural constraints from solid-state NMR and cryo-EM led us to an oligomer model with a hollow square cylinder shape capable of conducting ions when embedded in a lipid membrane. Based on the model, we argue that geometric frustration may distinguish the assembly pathway that produces this oligomer from fibril-forming assembly pathways.Competing Interest StatementThe authors have declared no competing interest.