Polymorphic Triple β-Sheet Structures Contribute to Amide Hydrogen/Deuterium (H/D) Exchange Protection in the Alzheimer Amyloid β42 Peptide

Abstract

Background: Experimental structural elucidation of polymorphic amyloid ensembles is difficult. Results: We found a novel amyloid structural motif of a triple ␤-sheet by comparing computational and experimental H/D exchange. Conclusion:The triple ␤-sheet A␤42 has a minimal exposure of hydrophobic residues and is further stabilized by the E22Q (Dutch) mutation in Alzheimer disease. Significance: The finding helps to understand the Dutch mutation in Alzheimer disease.

Antiparallel Triple-strand Architecture for Prefibrillar Aβ42 Oligomers

“…These studies highlighted the structural importance of N-terminal region, which is likely structured in the amyloid fibrils of both A␤40 and A␤42. In the structural model of A␤42 oligomers, we also show that each A␤42 molecule consists of three ␤-strands at similar residue positions as previously found in A␤42 fibrils (52,65). At the tertiary structure level, however, three ␤-strands from the same A␤42 molecule participate in the same ␤-sheet in an antiparallel fashion.…”

“…Except for the N-terminal ␤-strand, the rest of the residues adopt a structure that is very similar to the antiparallel structure of A␤40 D23N fibrils (70). Although conceptually similar to the triple ␤-sheet models of Nussinov et al (65), this alternative model distinguishes itself in the N-terminal region, which folds back to the double ␤-sheet of the C-terminal region. In alternative model B (Fig.…”

“…In their model, each A␤42 molecule consists of three ␤-strands with two turn regions: one at residues 25-29, and the other one at residues 9 -14. Each ␤-strand participates in a different ␤-sheet in the triple ␤-sheet structure, which has a better correlation with the hydrogen exchange data than the double ␤-sheet structure (65). The triple ␤-sheet structure has been previously reported for A␤40 fibrils based on solid-state NMR data (66).…”

“…Nussinov et al previously modeled various triple ␤-sheet structures for A␤42 amyloid (65). In their model, each A␤42 molecule consists of three ␤-strands with two turn regions: one at residues 25-29, and the other one at residues 9 -14.…”

A new structural model of Alzheimer’s Aβ42 fibrils based on electron paramagnetic resonance data and Rosetta modeling

“…Mutagenesis to introduce β-sheet breakers such as proline has also been used to identify β-strand regions in Aβ42 fibrils (Morimoto et al, 2004). Electron microscopy (Schmidt et al, 2015; Zhang et al, 2009) and computational approaches (Ma and Nussinov, 2011) have also been used to model the structure of Aβ42 fibrils. Recently, Xiao et al (2015) reported a structure of Aβ42 fibrils based on solid-state NMR constraints and molecular dynamics simulations.…”