Extracellular interface between APP and Nicastrin regulates A? length and response to ?-secretase modulators.

ABSTRACT: ?-Secretase complexes (GSECs) are multimeric membrane proteases involved in a variety of physiological processes and linked to Alzheimer's disease (AD). Presenilin (PSEN, catalytic subunit), Nicastrin (NCT), Presenilin Enhancer 2 (PEN-2), and Anterior Pharynx Defective 1 (APH1) are the essential subunits of GSECs. Mutations in PSEN and the Amyloid Precursor Protein (APP) cause early-onset AD GSECs successively cut APP to generate amyloid-? (A?) peptides of various lengths. AD-causing mutations destabilize GSEC-APP/A?n interactions and thus enhance the production of longer A?s, which elicit neurotoxic events underlying pathogenesis. Here, we investigated the molecular strategies that anchor GSEC and APP/A?n during the sequential proteolysis. Our studies reveal that a direct interaction between NCT ectodomain and APPC99 influences the stability of GSEC-A?n assemblies and thereby modulates A? length. The data suggest a potential link between single-nucleotide variants in NCSTN and AD risk. Furthermore, our work indicates that an extracellular interface between the protease (NCT, PSEN) and the substrate (APP) represents the target for compounds (GSMs) modulating A? length. Our findings may guide future rationale-based drug discovery efforts.

SUBMITTER: Petit D 

PROVIDER: S-EPMC6576158 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature