Molecular basis for different substrate-binding sites and chaperone functions of the BRICHOS domain.
BRICHOS
fibrillar and amorphous aggregation
molecular chaperone
oligomer model
Journal
Protein science : a publication of the Protein Society
ISSN: 1469-896X
Titre abrégé: Protein Sci
Pays: United States
ID NLM: 9211750
Informations de publication
Date de publication:
Jul 2024
Jul 2024
Historique:
revised:
10
05
2024
received:
06
02
2024
accepted:
13
05
2024
medline:
12
6
2024
pubmed:
12
6
2024
entrez:
12
6
2024
Statut:
ppublish
Résumé
Proteins can misfold into fibrillar or amorphous aggregates and molecular chaperones act as crucial guardians against these undesirable processes. The BRICHOS chaperone domain, found in several otherwise unrelated proproteins that contain amyloidogenic regions, effectively inhibits amyloid formation and toxicity but can in some cases also prevent non-fibrillar, amorphous protein aggregation. Here, we elucidate the molecular basis behind the multifaceted chaperone activities of the BRICHOS domain from the Bri2 proprotein. High-confidence AlphaFold2 and RoseTTAFold predictions suggest that the intramolecular amyloidogenic region (Bri23) is part of the hydrophobic core of the proprotein, where it occupies the proposed amyloid binding site, explaining the markedly reduced ability of the proprotein to prevent an exogenous amyloidogenic peptide from aggregating. However, the BRICHOS-Bri23 complex maintains its ability to form large polydisperse oligomers that prevent amorphous protein aggregation. A cryo-EM-derived model of the Bri2 BRICHOS oligomer is compatible with surface-exposed hydrophobic motifs that get exposed and come together during oligomerization, explaining its effects against amorphous aggregation. These findings provide a molecular basis for the BRICHOS chaperone domain function, where distinct surfaces are employed against different forms of protein aggregation.
Substances chimiques
Molecular Chaperones
0
Adaptor Proteins, Signal Transducing
0
ITM2B protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e5063Subventions
Organisme : Alzheimer's Association Research Grant (U.S.)
Organisme : Vetenskapsrådet
Organisme : Olle Engkvists Stiftelse
Organisme : Petrus and Augusta Hedlunds Stiftelse
Organisme : Åke Wibergs stiftelse
Organisme : the Swedish Alzheimer Foundation
Organisme : Åhlén Stiftelsens
Organisme : Karolinska Institutet Research Foundation Grant
Organisme : Stiftelsen för Gamla Tjänarinnor
Organisme : Stiftelsen Sigurd och Elsa Goljes Minne
Organisme : Loo and Hans Osterman Foundation for Medical Research
Organisme : Geriatric Diseases Foundation at Karolinska Institutet
Organisme : Gun and Bertil Stohne's Foundation
Organisme : Magnus Bergvall Foundation
Organisme : FORMAS
Organisme : China Scholarship Council
Organisme : China Association for Science and Technology
Informations de copyright
© 2024 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.
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