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TitleApo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform.
Journal, issue, pagesNat Commun, Vol. 15, Issue 1, Page 4479, Year 2024
Publish dateMay 27, 2024
AuthorsIvica Odorčić / Mohamed Belal Hamed / Sam Lismont / Lucía Chávez-Gutiérrez / Rouslan G Efremov /
PubMed AbstractDeposition 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 ...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, and identifies three other H-bonding interactions that, according to functional validation, are required for substrate recognition and efficient sequential catalysis.
External linksNat Commun / PubMed:38802343 / PubMed Central
MethodsEM (single particle)
Resolution3.3 - 3.4 Å
Structure data

17112

8oqy

EMDB-17112, PDB-8oqy:
Structure of apo form of human gamma-secretase PSEN1 APH-1B isoform reconstituted into lipid nanodisc
Method: EM (single particle) / Resolution: 3.3 Å

17113

8oqz

EMDB-17113, PDB-8oqz:
Structure of human gamma-secretase PSEN1 APH-1B isoform reconstituted into lipid nanodisc in complex with Ab46
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-PC1:
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / intramembrane proteolysis / protease / di-aspartyl protease / Alzheimer's disease / complex / amyloid beta

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