Self-replication of A/342 aggregates occurs on small and isolated fibril sites

• 成果类型: Article
• 署名作者: Curk, Samo; Krausser, Johannes; Meisl, Georg; Frenkel, Daan; Linse, Sara; Michaels, Thomas C. T.; Knowles, Tuomas P. J.; Saric, Andela
• 署名单位: Institute of Science & Technology - Austria; University of London; University College London; University of Cambridge; Lund University; Swiss Federal Institutes of Technology Domain; ETH Zurich
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9148
• DOI: 10.1073/pnas.2220075121
• 发表日期: 2024-02-13
• 关键词: secondary nucleation; kinetics; mechanisms; peptide; modulation; a-beta-40; SURFACES; BEHAVIOR

摘要

Self -replication of amyloid fibrils via secondary nucleation is an intriguing physicochemical phenomenon in which existing fibrils catalyze the formation of their own copies. The molecular events behind this fibril surface -mediated process remain largely inaccessible to current structural and imaging techniques. Using statistical mechanics, computer modeling, and chemical kinetics, we show that the catalytic structure of the fibril surface can be inferred from the aggregation behavior in the presence and absence of a fibril -binding inhibitor. We apply our approach to the case of Alzheimer's A/342 amyloid fibrils formed in the presence of proSP-C Brichos inhibitors. We find that self -replication of A/342 fibrils occurs on small catalytic sites on the fibril surface, which are far apart from each other, and each of which can be covered by a single Brichos inhibitor.