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Cited by 15Alzheimer's disease research and treatmentsEnzyme Structure and FunctionDementia and Cognitive Impairment Research

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

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Odorčić, Ivica, Hamed, Mohamed Belal, Lismont, Sam, Chávez-Gutiérrez, Lucía, Efremov, Rouslan G.·2024·Nature Communications
DOI 10.1038/s41467-024-48776-2

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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.

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Metadata

Authors
Odorčić, I., Hamed, M. B., Lismont, S., Chávez-Gutiérrez, L., & Efremov, R. G.
Affiliations
  • Vrije Universiteit Brussel (BE)
  • VIB-KU Leuven Center for Brain & Disease Research (BE)
Corresponding author
Efremov, Rouslan G.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-05-27
Volume
15
Issue
1
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-48776-2
OpenAlex
W4399053952
Cited by
15
References
4
Citations by year
2026: 3 · 2025: 7 · 2024: 5
FWCI
4.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Lirias (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Fonds Wetenschappelijk Onderzoek (G0H5916N, G054617N, G0B2519N, G008023N)
  • Vlaams Instituut voor Biotechnologie
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
gamma-secretase, amyloid-beta processing, presenilin 1, Alzheimer's disease, amyloid precursor protein, substrate recognition, allosteric regulation, lipid nanodiscs, cryo-EM structure, hydrogen bonding

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