An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations.

ABSTRACT: Amyloid precursor protein (APP) is cleaved and processed sequentially by γ-secretase yielding amyloid β (Aβ) peptides of different lengths. Longer Aβ peptides are associated with the formation of neurotoxic plaques related to Alzheimer's disease. Based on the APP substrate-bound structure of γ-secretase, we investigated the enzyme-substrate interaction using molecular dynamics simulations and generated model structures that represent the sequentially cleaved intermediates during the processing reaction. The simulations indicated an internal docking site providing strong enzyme-substrate packing interaction. In the enzyme-substrate complex, it is located close to the region where the helical conformation of the substrate is interrupted and continues toward the active site in an extended con

SUBMITTER: Chen SY 

PROVIDER: S-EPMC9279352 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature