γ-Secretase Studied by Atomistic Molecular Dynamics Simulations: Global Dynamics, Enzyme Activation, Water Distribution and Lipid Binding.

ABSTRACT: γ-secretase, an intramembrane-cleaving aspartyl protease is involved in the cleavage of a large number of intramembrane proteins. The most prominent substrate is the amyloid precursor protein, whose proteolytic processing leads to the production of different amyloid Aβ peptides. These peptides are known to form toxic aggregates and may play a key role in Alzheimer's disease (AD). Recently, the three-dimensional structure of γ-secretase has been determined via Cryo-EM, elucidating the spatial geometry of this enzyme complex in different functional states. We have used molecular dynamics (MD) simulations to study the global dynamics and conformational transitions of γ-secretase, as well as the water and lipid distributions in and around the transmembrane domains in atomic detail. Simulations

SUBMITTER: Hitzenberger M 

PROVIDER: S-EPMC6328467 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature