Issue 7, 2013

PtCl2(phen) disrupts the metal ions binding to amyloid-β peptide

Abstract

Platinum phenanthroline complexes have been found to inhibit Aβ aggregation and reduce Aβ caused neurotoxicity. Our previous results revealed the synergistic roles of phenanthroline ligand and Pt(II) coordination in the inhibition of Aβ aggregation. In this work, the reactions of PtCl2(phen) with metal bound Aβ complexes were investigated. HPLC results show that the copper coordination decreases the reaction rate of PtCl2(phen) with Aβ1–16 and influences the distribution of products on HPLC profiles. EPR results reveal that Cu2+ remains coordinated to the Aβ peptide upon the binding of [Pt(phen)]2+, however, the Cu2+ coordination sites are changed. The formation of bimetallic coordination complex [Pt(phen)+Aβ1–16+CuII] was confirmed by ESI-MS. Tandem MS analysis shows that, similar to the reaction of apo-Aβ peptide, the His6/His14 chelation is also the preferred binding mode for [Pt(phen)]2+ in the presence of copper ions. EPR spectra suggest that the binding of [Pt(phen)]2+ alters the copper coordination from mode I to mode II in Aβ. Tandem MS analysis indicates that His13 and N-terminal amine could be involved in the Cu2+ coordination in the bimetallic adduct. Similar results were observed in the reaction of Zn2+ bound Aβ peptide, although the different zinc binding residues were detected in the bimetallic complex. These results indicate that the binding of platinum complex disturbs the most favorable coordination sphere of Cu2+/Zn2+ and turns these metal ions to the secondary coordination site on Aβ. The release of Cu2+/Zn2+ occurs at low pH. This result suggests that the binding of [Pt(phen)]2+ scaffold could interfere with the binding of Zn2+ and Cu2+ to Aβ, thus reducing the metal-induced Aβ aggregation and toxicity.

Graphical abstract: PtCl2(phen) disrupts the metal ions binding to amyloid-β peptide

Supplementary files

Article information

Article type
Paper
Submitted
23 dec 2012
Accepted
05 apr 2013
First published
08 apr 2013

Metallomics, 2013,5, 879-887

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