Effect of pathogenic mutations on the structure and dynamics of Alzheimer’s Aβ42-amyloid oligomers |
| |
Authors: | Kristin Kassler Anselm H C Horn Heinrich Sticht |
| |
Institution: | 1. Bioinformatik, Institut für Biochemie, Friedrich-Alexander-Universit?t Erlangen-Nürnberg, Fahrstra?e 17, 91054, Erlangen, Germany
|
| |
Abstract: | Converging lines of evidence suggest that soluble Aβ-amyloid oligomers play a pivotal role in the pathogenesis of Alzheimer’s
disease, and present direct effectors of synaptic and cognitive dysfunction. Three pathological E22-Aβ-amyloid point mutants
(E22G, E22K, E22Q) and the deletion mutant E22Δ exhibit an enhanced tendency to form prefibrillar aggregates. The present
study assessed the effect of these four mutations using molecular dynamics simulations and subsequent structural and energetic
analyses. Our data shows that E22 plays a unique role in wild type Aβ, since it has a destabilising effect on the oligomer
structure due to electrostatic repulsion between adjacent E22 side chains. Mutations in which E22 is replaced by an uncharged
residue result in higher oligomer stability. This effect is also observed to a lesser extent for the E22K mutation and is
consistent with its lower pathogenicity compared to other mutants. Interestingly, deletion of E22 does not destroy the amyloid
fold but is compensated by local changes in the backbone geometry that allow the preservation of a structurally important
salt bridge. The finding that all mutant oligomers investigated exhibit higher internal stability than the wild type offers
an explanation for the experimentally observed enhanced oligomer formation and stability. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|