Identification of a novel high affinity copper binding site in the APP(145–155) fragment of amyloid precursor protein

Abstract

The copper(II) binding features of the APP(145-155) and APP(145-157) fragments of the amyloid precursor protein, Ac-Glu-Thr-His-Leu-His-Trp-His-Thr-Val-Ala-Lys-NH2 and Ac-Glu-Thr-His-Leu-His-Trp-His-Thr-Val-Ala-Lys-Glu-Thr-NH2 were studied by NMR spectroscopy and NMR findings were supported by UV-vis, CD and EPR spectra. Potentiometric measurements were performed only for the more soluble Ac-Glu-Thr-His-Leu-His-Trp-His-Thr-Val-Ala-Lys-Glu-Thr-NH2 peptide fragment. The following was shown: (i) the imidazole rings of all the three His residues are involved in metal coordination; (ii) metal binding induces ionisation of Leu-148 and His-149 amide nitrogens that complete the donor set to copper(II) in the species dominant at neutral pH; (iii) the unusual coordination scheme of the His-Xxx-His-Xxx-His consensus sequence justifies the high specificity for Cu(II) when compared to SOD-like or albumin-like peptides or even in amyloid Abeta fragments. The present findings may represent the key for interpreting the observed requirement of His residues conservation for the redox cycling between Cu(II) and Cu(I) by soluble APP.

A minimalist chemical model of matrix metalloproteinases — Can small peptides mimic the more rigid metal binding sites of proteins?

“…Nevertheless, a number of studies are reported in the literature dealing with short in-chain sequences as putative metal binding sites of e.g. amyloid precursor protein [14], the repeat sequences of Cap43 [15] and histidine-rich (glyco)proteins [16], the histon H2A protein [17] or the metal-transport protein IRT1 [18]. In spite of the limited analogy between such peptides and the native proteins, in the absence of structural information such studies are of great values, since even the identification of putative metal binding sites may improve our knowledge on the functioning of the given proteins.…”

“…Such metal binding sites are obviously difficult to mimic by small peptides. However, a number of proteins possess relatively short histidine-rich sequences with strong metal binding ability, which substantially contributes to the function of the given macromolecule [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Beside the well known human serum albumin (HSA) [1], probably the prion proteins (PrP) [2] are the most studied examples of such sequences.…”

Tuning the coordination properties of multi-histidine peptides by using a tripodal scaffold: solution chemical study and catechol oxidase mimicking

“…Linear peptides have long since been used to mimic the metal binding sites of metalloproteins [1][2][3][4][5][6][7] and metalloenzymes. [8][9][10][11][12] Previously, we also studied some histidine-rich peptides in order to create similar metal ion environment to native enzymes.…”

Histidine‐containing host‐defence skin peptides of anurans bind Cu2+. An electrospray ionisation mass spectrometry and computational modelling study

“…[15] Copper activates arginine vasopressin action and is a major component in contraceptive devices. [16] Cu 2+ binds to prion proteins, [17,18] and to prionrelated amyloid peptides. [19] Cu 2+ chelates inhibit the replication of human [20] and avian [21] influenza viruses, and AIDS viruses.…”