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A\u03b2s are generated through sequential proteolysis of the amyloid precursor protein by the \u03b3-secretase complexes (GSECs). A\u03b2 peptide length, modulated by the Presenilin (PSEN) and APH-1 subunits of GSEC, is critical for Alzheimer\u2019s pathogenesis. Despite high relevance, mechanistic understanding of the proteolysis of A\u03b2, 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\u03b246 substrate without cross-linking. We find that three non-conserved and structurally divergent APH-1 regions establish contacts with PSEN1, and that substrate-binding induces concerted rearrangements in one of the identified PSEN1\/APH-1 interfaces, providing structural basis for APH-1 allosteric-like effects. In addition, the GSEC-A\u03b246 structure reveals an interaction between A\u03b246 and loop 1\n                    <jats:sup>PSEN1<\/jats:sup>\n                    , and identifies three other H-bonding interactions that, according to functional validation, are required for substrate recognition and efficient sequential catalysis.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-48776-2","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T03:02:27Z","timestamp":1716778947000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Apo and A\u03b246-bound \u03b3-secretase structures provide insights into amyloid-\u03b2 processing by the APH-1B isoform"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8121-3803","authenticated-orcid":false,"given":"Ivica","family":"Odor\u010di\u0107","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6383-4147","authenticated-orcid":false,"given":"Mohamed Belal","family":"Hamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Lismont","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc\u00eda","family":"Ch\u00e1vez-Guti\u00e9rrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7516-8658","authenticated-orcid":false,"given":"Rouslan G.","family":"Efremov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,27]]},"reference":[{"key":"48776_CR1","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","volume":"397","author":"P Scheltens","year":"2021","unstructured":"Scheltens, P. et al. 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