APP substrate ectodomain defines amyloid-β peptide length by restraining γ-secretase processivity and facilitating product release.

ABSTRACT: Sequential proteolysis of the amyloid precursor protein (APP) by γ-secretases generates amyloid-β (Aβ) peptides and defines the proportion of short-to-long Aβ peptides, which is tightly connected to Alzheimer's disease (AD) pathogenesis. Here, we study the mechanism that controls substrate processing by γ-secretases and Aβ peptide length. We found that polar interactions established by the APP_C99 ectodomain (ECD), involving but not limited to its juxtamembrane region, restrain both the extent and degree of γ-secretases processive cleavage by destabilizing enzyme-substrate interactions. We show that increasing hydrophobicity, via mutation or ligand binding, at APP_C99 -ECD attenuates substrate-driven product release and rescues the effects of Alzheimer's disease-associa

SUBMITTER: Koch M 

PROVIDER: S-EPMC10690472 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature