Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/114080
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Type: Journal article
Title: The human amyloid precursor protein binds copper ions dominated by picomolar-affinity site in the helix-rich E2 domain
Author: Young, T.
Pukala, T.
Cappai, R.
Wedd, A.
Xiao, Z.
Citation: Biochemistry, 2018; 57(28):4165-4176
Publisher: American Chemical Society
Issue Date: 2018
ISSN: 0006-2960
1520-4995
Statement of
Responsibility: 
Tessa R. Young, Tara L. Pukala, Roberto Cappai, Anthony G. Wedd, and 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.
Keywords: Humans; Copper; Amyloid beta-Protein Precursor; Crystallography, X-Ray; Binding Sites; Protein Binding; Models, Molecular; Protein Domains; Serum Albumin, Human
Description: Published: June 12, 2018
Rights: © 2018 American Chemical Society
RMID: 0030093256
DOI: 10.1021/acs.biochem.8b00572
Grant ID: http://purl.org/au-research/grants/arc/DP130100728
Appears in Collections:Chemistry publications

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