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Issue 28, 2020
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Molecular crowding effects on the biochemical properties of amyloid β–heme, Aβ–Cu and Aβ–heme–Cu complexes

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Abstract

Heme as a cofactor has been proposed to bind with β-amyloid peptide (Aβ) and the formed Aβ–heme complex exhibits enhanced peroxidase-like activity. So far, in vitro studies on the interactions between heme, Cu and Aβ have been exclusively performed in dilute solution. However, the intracellular environment is highly crowded with biomolecules. Therefore, exploring how Aβ–heme–Cu complexes behave under molecular crowding conditions is critical for understanding the mechanism of Aβ neurotoxicity in vivo. Herein, we selected PEG-200 as a crowding agent to mimic the crowded cytoplasmic environment for addressing the contributions of crowded physiological environments to the biochemical properties of Aβ–heme, Aβ–Cu and Aβ–heme–Cu complexes. Surprisingly, experimental studies and theoretical calculations revealed that molecular crowding weakened the stabilization of the Aβ–heme complex and decreased its peroxidase activity. Our data attributed this consequence to the decreased binding affinity of heme to Aβ as a result of the alterations in water activity and Aβ conformation. Our findings highlight the significance of hydration effects on the interaction of Aβ–heme and Aβ–Cu and their peroxidase activities. Molecular crowding inside cells may potentially impose a positive effect on Aβ–Cu but a negative effect on the interaction of Aβ with heme. This indicates that Aβ40–Cu but not Aβ40–heme may play more important roles in the oxidative damage in the etiology of AD. Therefore, this work provides a new clue for understanding the oxidative damage occurring in AD.

Graphical abstract: Molecular crowding effects on the biochemical properties of amyloid β–heme, Aβ–Cu and Aβ–heme–Cu complexes

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Supplementary files

Article information


Submitted
20 Feb 2020
Accepted
02 Jul 2020
First published
02 Jul 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 7479-7486
Article type
Edge Article

Molecular crowding effects on the biochemical properties of amyloid β–heme, Aβ–Cu and Aβ–heme–Cu complexes

M. Li, Z. Liu, J. Ren and X. Qu, Chem. Sci., 2020, 11, 7479
DOI: 10.1039/D0SC01020K

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