Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 10, Pages 5160-5167Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1916944117
Keywords
copper; amyloid-beta; small molecule; copper-O-2 chemistry; residue-specific modifications
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Funding
- 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]
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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.
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