Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform

Ivica Odorčić, Mohamed Belal Hamed, Sam Lismont, Lucía Chávez-Gutiérrez () and Rouslan G. Efremov ()
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Ivica Odorčić: VIB
Mohamed Belal Hamed: Herestraat 49 box 602
Sam Lismont: Herestraat 49 box 602
Lucía Chávez-Gutiérrez: Herestraat 49 box 602
Rouslan G. Efremov: VIB

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: 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 1PSEN1, and identifies three other H-bonding interactions that, according to functional validation, are required for substrate recognition and efficient sequential catalysis.

Date: 2024
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DOI: 10.1038/s41467-024-48776-2

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