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The Human Amyloid Precursor Protein Binds Copper Ions Dominated by a Picomolar Affinity Site in the Helix-Rich E2 Domain

Young, Tessa R.; Pukala, Tara L.; Cappai, Roberto; Wedd, Anthony G.; Xiao, Zhiguang

The Human Amyloid Precursor Protein Binds Copper Ions Dominated by a Picomolar Affinity Site in the Helix-Rich E2 Domain Thumbnail


Authors

Tara L. Pukala

Roberto Cappai

Anthony G. Wedd

Zhiguang Xiao



Abstract

A manifestation of Alzheimer’s disease (AD) is the aggregation in the brain of amyloid β (Aβ) peptides derived from the amyloid precursor protein (APP). APP has been linked to modulation of normal copper homeostasis, while dysregulation of Aβ production and clearance has been associated with disruption of copper balance. However, quantitative copper chemistry on APP is lacking, in contrast to the plethora of copper chemistry available for Aβ peptides. The soluble extracellular protein domain sAPPα (molar mass including post-translational modifications of ∼100 kDa) has now been isolated in good yield and high quality. It is known to feature several copper binding sites with different affinities. However, under Cu-limiting conditions, it binds either Cu(I) or Cu(II) with picomolar affinity at a single site (labeled M1) that is located within the APP E2 subdomain. M1 in E2 was identified previously by X-ray crystallography as a Cu(II) site that features four histidine side chains (H313, H386, H432, and H436) as ligands. The presence of CuII(His)4 is confirmed in solution at pH ≤7.4, while Cu(I) binding involves either the same ligands or a subset. The binding affinities are pH-dependent, and the picomolar affinities for both Cu(I) and Cu(II) at pH 7.4 indicate that either oxidation state may be accessible under physiological conditions. Redox activity was observed in the presence of an electron donor (ascorbate) and acceptor (dioxygen). A critical analysis of the potential biological implications of these findings is presented.

Citation

Young, T. R., Pukala, T. L., Cappai, R., Wedd, A. G., & Xiao, Z. (2018). The Human Amyloid Precursor Protein Binds Copper Ions Dominated by a Picomolar Affinity Site in the Helix-Rich E2 Domain. Biochemistry, 57(28), 4165-4176. https://doi.org/10.1021/acs.biochem.8b00572

Journal Article Type Article
Acceptance Date May 21, 2018
Online Publication Date Jun 12, 2018
Publication Date Jul 17, 2018
Deposit Date Jun 21, 2018
Publicly Available Date Mar 28, 2024
Journal Biochemistry.
Print ISSN 0006-2960
Electronic ISSN 1520-4995
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 57
Issue 28
Pages 4165-4176
DOI https://doi.org/10.1021/acs.biochem.8b00572

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Copyright Statement
Supplementary Information This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acs.biochem.8b00572.





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