αB-Crystallin Chaperone Inhibits Aβ Aggregation by Capping the β‑Sheet-Rich Oligomers and Fibrils

Inhibiting the cytotoxicity of amyloid aggregation by endogenous proteins is a promising strategy against degenerative amyloid diseases due to their intrinsically high biocompatibility and low immunogenicity. In this study, we investigated the inhibition mechanism of the structured core region of αB...

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Bibliographic Details
Published in:The journal of physical chemistry. B 2020-11, Vol.124 (45), p.10138-10146
Main Authors: Sun, Yunxiang, Ding, Feng
Format: Article
Language:English
Subjects:
Amyloid
Amyloid beta-Peptides
B: Biophysics
Physical Chemistry of Biological Systems and Biomolecules
Crystallins
Molecular Chaperones
Protein Conformation, beta-Strand
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Summary:Inhibiting the cytotoxicity of amyloid aggregation by endogenous proteins is a promising strategy against degenerative amyloid diseases due to their intrinsically high biocompatibility and low immunogenicity. In this study, we investigated the inhibition mechanism of the structured core region of αB-crystallin (αBC) against Aβ fibrillization using discrete molecular dynamics simulations. Our computational results recapitulated the experimentally observed Aβ binding sites in αBC and suggested that αBC could bind to various Aβ aggregate species during the aggregation processincluding monomers, dimers, and likely other high molecular weight oligomers, protofibrils, and fibrilsby capping the exposed β-sheet elongation surfaces. Thus, the nucleation of Aβ oligomers into fibrils and the fibril growth could be inhibited. Mechanistic insights obtained from our systematic computational studies may aid in the development of novel therapeutic strategies to modulate the aggregation of pathological, amyloidogenic protein in degenerative diseases.
ISSN:1520-6106
1520-5207
DOI:10.1021/acs.jpcb.0c07256