1. Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform.
- Author
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Odorčić I, Hamed MB, Lismont S, Chávez-Gutiérrez L, and Efremov RG
- Subjects
- Humans, Endopeptidases metabolism, Endopeptidases chemistry, Amyloid beta-Protein Precursor metabolism, Amyloid beta-Protein Precursor chemistry, Protein Binding, Protein Isoforms metabolism, Protein Isoforms chemistry, Alzheimer Disease metabolism, Peptide Fragments metabolism, Peptide Fragments chemistry, Peptide Hydrolases metabolism, Peptide Hydrolases chemistry, Models, Molecular, Proteolysis, Amyloid Precursor Protein Secretases metabolism, Amyloid Precursor Protein Secretases chemistry, Presenilin-1 metabolism, Presenilin-1 chemistry, Presenilin-1 genetics, Cryoelectron Microscopy, Amyloid beta-Peptides metabolism, Amyloid beta-Peptides chemistry, Membrane Proteins metabolism, Membrane Proteins chemistry
- Abstract
Deposition of amyloid-β (Aβ) peptides in the brain is a hallmark of Alzheimer's disease. Aβs are generated through sequential proteolysis of the amyloid precursor protein by the γ-secretase complexes (GSECs). Aβ peptide length, modulated by the Presenilin (PSEN) and APH-1 subunits of GSEC, is critical for Alzheimer's pathogenesis. Despite high relevance, mechanistic understanding of the proteolysis of Aβ, 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 Aβ46 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-Aβ46 structure reveals an interaction between Aβ46 and loop 1
PSEN1 , and identifies three other H-bonding interactions that, according to functional validation, are required for substrate recognition and efficient sequential catalysis., (© 2024. The Author(s).)- Published
- 2024
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