Dissecting conformational changes in APP's transmembrane domain linked to ?-efficiency in familial Alzheimer's disease.

ABSTRACT: The mechanism by which familial Alzheimer's disease (FAD) mutations within the transmembrane domain (TMD) of the Amyloid Precursor Protein (APP) affect ?-endoproteolysis is only poorly understood. Thereby, mutations in the cleavage domain reduce ?-efficiency of ?-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 ?-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 ?-cleavage, (ii) key sites consistent with experimentally determined docking sites, and (iii) the distinction between mutants and wild-type.

SUBMITTER: Gotz A 

PROVIDER: S-EPMC6028146 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature