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J. Am. Chem. Soc., Published inissue 2 February 2022 | https://doi.org/10.1021/jacs.1c10173 Kinetic Modulation of Amyloid-β (1–42) Aggregation and Toxicity by Structure-Based Rational Design

Dongjoon Im^†,‡,§, Chae Eun Heo^†, Myung Kook Son^†,‡,§, Chae Ri Park^†,‡,§, Hugh I. Kim^†,‡,§*, and Jeong-Mo Choi^‖*

^†Department of Chemistry, Korea University, Seoul 02841, Republic of Korea ^‡Center for Proteogenome Research, Korea University, Seoul 02841, Republic of Korea ^§Single Cell Analysis Laboratory, Korea University, Seoul 02841, Republic of Korea ^‖Department of Chemistry, Pusan National University, Busan 46241, Republic of Korea

^*Corresponding author.

Abstract

Several point mutations can modulate protein structure and dynamics, leading to different natures. Especially in the case of amyloidogenic proteins closely related to neurodegenerative diseases, structural changes originating from point mutations can affect fibrillation kinetics. Herein, we rationally designed mutant candidates to inhibit the fibrillation process of amyloid-β with its point mutants through multistep in silico analyses. Our results showed that the designed mutants induced kinetic self-assembly suppression and reduced the toxicity of the aggregate. A multidisciplinary biophysical approach with small-angle X-ray scattering, ion mobility-mass spectrometry, mass spectrometry, and additional in silico experiments was performed to reveal the structural basis associated with the inhibition of fibril formation. The structure-based design of the mutants with suppressed self-assembly performed in this study could provide a different perspective for modulating amyloid aggregation based on the structural understanding of the intrinsically disordered proteins.

논문정보

형식Research article
게재일2022년 02월 (BRIC 등록일 2022-02-16)
연구진국내 연구진
분야 생명과학 > 구조생물 및 생물물리학

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