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 (GSECs) generates amyloid-β (Aβ) 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 controlling substrate processing by GSECs and defining product length. We found that polar interactions established by the APPC99 ectodomain (ECD), involving but not limited to its juxtamembrane region, restrain both the extent and degree of GSEC processive cleavage by destabilizing enzyme-substrate (E-S) interactions. We show that increasing hydrophobicity at APPC99 ECD - due to mutation or ligand binding - attenuates this substrate-driven product release mechanism, and rescues the effects that AD pathogenic variants exert on A

SUBMITTER: Prof. Lucía Chávez-Gutiérrez 

PROVIDER: S-SCDT-10_15252-EMBJ_2023114372 | biostudies-other |

REPOSITORIES: biostudies-other