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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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JACS Au 2023年第4期3卷 1065-1075页

作者： Im, Dongjoon Kim, Soohyeong Yoon, Gyusub Hyun, Da Gyeong Eom, Yu-Gon Lee, Ye Eun Sohn, Chang Ho Choi, Jeong-Mo Kim, Hugh I. Department of Chemistry Korea University Seoul 02841 South Korea Center for Proteogenome Research Korea University Seoul 02841 South Korea Single Cell Analysis Laboratory Korea University Seoul 02841 South Korea Department of Chemistry Pusan National University Busan 46241 South Korea Center for Nanomedicine Institute for Basic Science (IBS) Seoul 03722 South Korea Graduate Program in Nanobiomedical Engineering Advanced Science Institute Yonsei University Seoul 03722 South Korea Chemistry Institute for Functional Materials Pusan National University Busan 46241 South Korea

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. © 2023 The Authors. Published by American Chemical Society.

关键词： aggregation conformation inhibitors oligomers peptides and proteins

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Correction to: Channel-mediated astrocytic glutamate modulates hippocampal synaptic plasticity by activating postsynaptic NMDA receptors

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Molecular brain 2021年第1期14卷 103页

作者： Hyungju Park Kyung-Seok Han Jinsoo Seo Jaekwang Lee Shashank M Dravid Junsung Woo Heejung Chun Sukhee Cho Jin Young Bae Heeyoung An Woohyun Koh Bo-Eun Yoon Rolando Berlinguer-Palmini Guido Mannaioni Stephen F Traynelis Yong Chul Bae Se-Young Choi C Justin Lee Center for Neural Science Korea Institute of Science and Technology (KIST) Seoul Korea. Neuroscience Program University of Science and Technology (UST) Daejeon Korea. Department of Physiology and Dental Research Institute Seoul National University School of Dentistry Seoul Korea. Department of Pharmacology Creighton University Omaha NE USA. Department of Oral Anatomy and Neurobiology School of Dentistry Kyungpook National University Daegu Korea. KU-KIST Graduate School of Converging Science and Technology Korea University 145 Anam-ro Seongbuk-gu Seoul 02841 Korea. Department of Nanobiomedical Science Dankook University Cheonan Korea. School of Electrical and Electronic Engineering Institute of Neuroscience Newcastle University Newcastle upon Tyne UK. Department of Pharmacology University of Florence Florence Italy. Department of Pharmacology Emory University Atlanta GA USA. Department of Physiology and Dental Research Institute Seoul National University School of Dentistry Seoul Korea. sychoi@snu.ac.kr. Center for Neural Science Korea Institute of Science and Technology (KIST) Seoul Korea. cjl@kist.re.kr. Neuroscience Program University of Science and Technology (UST) Daejeon Korea. cjl@kist.re.kr. KU-KIST Graduate School of Converging Science and Technology Korea University 145 Anam-ro Seongbuk-gu Seoul 02841 Korea. cjl@kist.re.kr.

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