Publication details for Dr Tessa YoungYoung, Tessa R., Pukala, Tara L., Cappai, Roberto, Wedd, Anthony G. & Xiao, Zhiguang (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.
- Publication type: Journal Article
- ISSN/ISBN: 0006-2960 (print), 1520-4995 (electronic)
- DOI: 10.1021/acs.biochem.8b00572
- Further publication details on publisher web site
- Durham Research Online (DRO) - may include full text
Author(s) from Durham
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.