Structure of γ-secretase (PSEN1/APH-1B) in complex with Aβ46 provides insights into amyloid-β processing and modulation by the APH-1B isoform

Deposition of amyloid-{beta} (A{beta}) peptides in the brain is a hallmark of Alzheimers disease. A{beta}s are generated through sequential proteolysis of the amyloid precursor protein by the {gamma}-secretase complexes (GSECs). A{beta} peptide length, which is modulated by the Presenilin (PSEN) and APH-1 subunits of GSEC, is critical for Alzheimers pathogenesis. Despite high relevance, mechanistic understanding of the proteolysis of A{beta}, and its modulation by APH-1, remain incomplete. Here, we report cryo-EM structures of human GSEC (PSEN1/APH-1B) reconstituted into lipid nanodiscs in apo form and in complex with the intermediate A{beta}46 substrate. We found a divergent APH-1 loop to be involved with PSEN1 in substrate-binding-induced concerted rearrangements. Upstream the catalytic site, A{beta}46 structure is similar to the endopeptidase substrates and is stabilised by polar interactions including a previously unseen interaction with PSEN1 loop1. The hybrid {beta}-sheet was not observed downstream the catalytic site.