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Decoding the Roles of Amyloid-β (1-42)’s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors

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Title
Decoding the Roles of Amyloid-β (1-42)’s Key Oligomerization Domains toward Designing Epitope-Specific Aggregation Inhibitors
Author(s)
Dongjoon Im; Soohyeong Kim; Gyusub Yoon; Da Gyeong Hyun; Yu-Gon Eom; Ye Eun Lee; Chang Ho Sohn; Jeong-Mo Choi; Hugh I. Kim
Publication Date
2023-04
Journal
JACS Au, v.3, no.4, pp.1065 - 1075
Publisher
American Chemical Society
Abstract
Fibrillar amyloid aggregates are the pathological hallmarks of multiple neurodegenerative diseases. The amyloid-β (1-42) protein, in particular, is a major component of senile plaques in the brains of patients with Alzheimer’s disease and a primary target for disease treatment. Determining the essential domains of amyloid-β (1-42) that facilitate its oligomerization is critical for the development of aggregation inhibitors as potential therapeutic agents. In this study, we identified three key hydrophobic sites (17LVF1932IGL34, and 41IA42) on amyloid-β (1-42) and investigated their involvement in the self-assembly process of the protein. Based on these findings, we designed candidate inhibitor peptides of amyloid-β (1-42) aggregation. Using the designed peptides, we characterized the roles of the three hydrophobic regions during amyloid-β (1-42) fibrillar aggregation and monitored the consequent effects on its aggregation property and structural conversion. Furthermore, we used an amyloid-β (1-42) double point mutant (I41N/A42N) to examine the interactions between the two C-terminal end residues with the two hydrophobic regions and their roles in amyloid self-assembly. Our results indicate that interchain interactions in the central hydrophobic region (17LVF19) of amyloid-β (1-42) are important for fibrillar aggregation, and its interaction with other domains is associated with the accessibility of the central hydrophobic region for initiating the oligomerization process. Our study provides mechanistic insights into the self-assembly of amyloid-β (1-42) and highlights key structural domains that facilitate this process. Our results can be further applied toward improving the rational design of candidate amyloid-β (1-42) aggregation inhibitors.
URI
https://pr.ibs.re.kr/handle/8788114/13297
DOI
10.1021/jacsau.2c00668
ISSN
2691-3704
Appears in Collections:
Center for Nanomedicine (나노의학 연구단) > 1. Journal Papers (저널논문)
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