Abstract
The mechanism by which familial Alzheimer’s disease (FAD) mutations within the transmembrane domain (TMD) of the Amyloid Precursor Protein (APP) affect ε-endoproteolysis is only poorly understood. Thereby, mutations in the cleavage domain reduce ε-efficiency of γ-secretase cleavage and some even shift entry into production lines. Since cleavage occurs within the TMD, a relationship between processing and TMD structure and dynamics seems obvious. Using molecular dynamic simulations, we dissect the dynamic features of wild-type and seven FAD-mutants into local and global components. Mutations consistently enhance hydrogen-bond fluctuations upstream of the ε-cleavage sites but maintain strong helicity there. Dynamic perturbation-response scanning reveals that FAD-mutants target backbone motions utilized in the bound state. Those motions, obscured by large-scale motions in the pre-bound state, provide (i) a dynamic mechanism underlying the proposed coupling between binding and ε-cleavage, (ii) key sites consistent with experimentally determined docking sites, and (iii) the distinction between mutants and wild-type.
Highlights
The onset and progression of Alzheimer’s disease (AD) are assumed to be linked to the accumulation of cell cytotoxic assemblies of β-amyloid (Aβ) peptides in the brain [1]
We studied the dynamics of model peptides of the C99-transmembrane domain (TMD) for WT and seven familial Alzheimer’s disease (FAD) mutants (Fig 1) by molecular dynamics (MD) simulations
None of the investigated parameters indicates persistent conversion to an alternative backbone fold. They suggest the existence of a continuum of helical conformations, where helices bend, twist and straighten, but remain α-helical on average. This is well-documented by low root mean-squared deviations (RMSD) of the average structures with respect to an ideal α-helix which vary between 1.04 Å and 1.27 Å
Summary
The onset and progression of Alzheimer’s disease (AD) are assumed to be linked to the accumulation of cell cytotoxic assemblies of β-amyloid (Aβ) peptides in the brain [1]. These Aβpeptides are products of sequential proteolytic processing of the amyloid precursor protein (APP), an integral type I membrane protein [2,3]. Ectodomain shedding of APP by β-secretase generates a 99 amino-acid long membrane-bound C-terminal fragment (C99). In the wild-type (WT) form, the most abundant fragment is Aβ40, while Aβ42 and Aβ38 show
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