Alexander August, Sabrina Hartmann, Sandra Schilling, Christine Müller-Renno, Tarik Begic, Antonio J Pierik, Christiane Ziegler, Stefan Kins
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引用次数: 0
Abstract
The amyloid precursor protein (APP) can be modulated by the binding of copper and zinc ions. Both ions bind with low nanomolar affinities to both subdomains (E1 and E2) in the extracellular domain of APP. However, the impact of ion binding on structural and mechanical trans-dimerization properties is yet unclear. Using a bead aggregation assay (BAA), we found that zinc ions increase the dimerization of both subdomains, while copper promotes only dimerization of the E1 domain. In line with this, scanning force spectroscopy (SFS) analysis revealed an increase in APP adhesion force up to three-fold for copper and zinc. Interestingly, however, copper did not alter the separation length of APP dimers, whereas high zinc concentrations caused alterations in the structural features and a decrease of separation length. Together, our data provide clear differences in copper and zinc mediated APP trans-dimerization and indicate that zinc binding might favor a less flexible APP structure. This fact is of significant interest since changes in zinc and copper ion homeostasis are observed in Alzheimer's disease (AD) and were reported to affect synaptic plasticity. Thus, modulation of APP trans-dimerization by copper and zinc could contribute to early synaptic instability in AD.
期刊介绍:
Biological Chemistry keeps you up-to-date with all new developments in the molecular life sciences. In addition to original research reports, authoritative reviews written by leading researchers in the field keep you informed about the latest advances in the molecular life sciences. Rapid, yet rigorous reviewing ensures fast access to recent research results of exceptional significance in the biological sciences. Papers are published in a "Just Accepted" format within approx.72 hours of acceptance.