Dissecting Conformational Changes in APP’s Transmembrane Domain Linked to ε-Efficiency in Familial Alzheimer’s Disease

The mechanism by which familial Alzheimers disease (FAD) mutations within the transmembrane domain (TMD) of the Amyloid Precursor Protein (APP) affect [a]-endoproteolysis is only poorly understood. Thereby, mutations in the cleavage domain reduce [a]-efficiency of a-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 hydrogen8 bond fluctuations upstream of the [a]-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 proposedcoupling between binding and [a]-cleavage, (ii) key sites consistent with experimentally determined docking sites, and (iii) the distinction between mutants and wild-type.