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

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 …