Identification of potential aggregation hotspots on Aβ42 fibrils blocked by the anti-amyloid chaperone-like BRICHOS domain.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
01 Feb 2024
01 Feb 2024
Historique:
received:
18
05
2023
accepted:
17
01
2024
medline:
2
2
2024
pubmed:
2
2
2024
entrez:
1
2
2024
Statut:
epublish
Résumé
Protein misfolding can generate toxic intermediates, which underlies several devastating diseases, such as Alzheimer's disease (AD). The surface of AD-associated amyloid-β peptide (Aβ) fibrils has been suggested to act as a catalyzer for self-replication and generation of potentially toxic species. Specifically tailored molecular chaperones, such as the BRICHOS protein domain, were shown to bind to amyloid fibrils and break this autocatalytic cycle. Here, we identify a site on the Aβ42 fibril surface, consisting of three C-terminal β-strands and particularly the solvent-exposed β-strand stretching from residues 26-28, which is efficiently sensed by a designed variant of Bri2 BRICHOS. Remarkably, while only a low amount of BRICHOS binds to Aβ42 fibrils, fibril-catalyzed nucleation processes are effectively prevented, suggesting that the identified site acts as a catalytic aggregation hotspot, which can specifically be blocked by BRICHOS. Hence, these findings provide an understanding how toxic nucleation events can be targeted by molecular chaperones.
Identifiants
pubmed: 38302480
doi: 10.1038/s41467-024-45192-4
pii: 10.1038/s41467-024-45192-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
965Informations de copyright
© 2024. The Author(s).
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