8OQZ

Structure of human gamma-secretase PSEN1 APH-1B isoform reconstituted into lipid nanodisc in complex with Ab46

Summary for 8OQZ

• Entry DOI: 10.2210/pdb8oqz/pdb
• EMDB information: 17113
• Descriptor: Nicastrin, Presenilin-1 CTF12, Gamma-secretase subunit APH-1B, ... (8 entities in total)
• Functional Keywords: intramembrane proteolysis, protease, di-aspartyl protease, alzheimer's disease, complex, amyloid beta, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 192299.82

Authors

Odorcic, I.,Chavez Gutierrez, L.,Efremov, R.G. (deposition date: 2023-04-12, release date: 2024-04-24, Last modification date: 2024-06-19)

Primary citation

Odorcic, I.,Hamed, M.B.,Lismont, S.,Chavez-Gutierrez, L.,Efremov, R.G.
Apo and A beta 46-bound gamma-secretase structures provide insights into amyloid-beta processing by the APH-1B isoform.
Nat Commun, 15:4479-4479, 2024

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

PubMed: 38802343
DOI: 10.1038/s41467-024-48776-2

Experimental method

ELECTRON MICROSCOPY (3.4 Å)