期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 10, 页码 5160-5167出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1916944117
关键词
copper; amyloid-beta; small molecule; copper-O-2 chemistry; residue-specific modifications
资金
- National Research Foundation of Korea (NRF) - Korean government [NRF-2016R1A5A1009405, NRF-2017R1A2B3002585, NRF-2015R1D1A1A01060188]
- Global Ph.D. Fellowship Program through the NRF - Ministry of Education [NRF-2019H1A2A1073754]
Neurotoxic implications of the interactions between Cu(I/II) and amyloid-beta (A beta) indicate a connection between amyloid cascade hypothesis and metal ion hypothesis with respect to the neurodegeneration associated with Alzheimer's disease (AD). Herein, we report a mechanistic strategy for modifying the first coordination sphere of Cu(II) bound to A beta utilizing a rationally designed peptide modifier, L1. Upon reacting with L1, a metal-binding histidine (His) residue, His14, in Cu(II)-A beta was modified through either covalent adduct formation, oxidation, or both. Consequently, the reactivity of L1 with Cu(II)-A beta was able to disrupt binding of Cu(II) to A beta and result in chemically modified A beta with altered aggregation and toxicity profiles. Our molecular-level mechanistic studies revealed that such L1-mediated modifications toward Cu(II)-A beta could stem from the molecule's ability to 1) interact with Cu(II)A beta and 2) foster copper-O-2 chemistry. Collectively, our work demonstrates the development of an effective approach to modify Cu(II)-A beta at a metal-binding amino acid residue and consequently alter A beta's coordination to copper, aggregation, and toxicity, supplemented with an in-depth mechanistic perspective regarding such reactivity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据