Abstract
Interaction of copper(II) and nickel(II) ions with the Ac-PHAAAGTHSMKHM-NH2 tridecapeptide containing the His85, His96 and His111 binding sites of human prion protein has been studied by various techniques. pH-potentiometry, UV–Vis and circular dichroism spectroscopy were applied to study the stoichiometry, stability and structure of the copper(II) and nickel(II) complexes, while HPLC-MS and MS/MS were used for identifying the products of copper(II) catalyzed oxidation. The copper binding ability of shorter fragments, namely the nonapeptide Ac-PHAAAGTHS-NH2 and pentapeptide Ac-PHAAA-NH2 have also been studied. The tridecapeptide is able to bind three equivalent of copper(II) ion, since the histidine residues behave as independent metal binding sites. Nevertheless, the metal binding ability of histidine residue mimicking the octarepeat domain (His85) is decreased, while the other parts of the peptide mimicking the histidines outside the octarepeat domain bind the copper ions in comparable concentration. On the other hand, this peptide is able to coordinate only two equivalents of nickel ion on the domains outside the octarepeat region. Furthermore the His96 binding site is more effective for the nickel ions. Both histidine and methionine residues are sensitive for oxidation, the oxidation of these residues are proved, and in the case of the histidine residues follows the order His96 > His85 ≫ His111.
Highlights
The human cellular prion protein, denoted PrPC consists of 231 amino acids
Due to the different coordination geometry of these metal ions differences may arise; in the case of the wild type prion protein fragments the metal binding preference was different; it shows a significant preference for Ni(II) binding at His96 residue (which is completely opposite to those reported for Cu(II) ion)
In the case of the histidine residues outside the octarepeat region His96 > His111 was reported for nickel(II) and the opposite trend for copper(II), while the histidine residue in the octarepeat region has smaller metal binding ability with both metal ions
Summary
The human cellular prion protein, denoted PrPC consists of 231 amino acids. PrPC can be divided into two distinct regions: a flexible Nterminal region that is essentially unstructured and a C-terminal region comprising three α-helical structures and two small anti-parallel βsheet structures [1,2]. The binding preference of the wild type prion protein is well-known from earlier studies These fragments contain several side chains which may have an effect on the complex formation processes even though they are far from the metal binding sites. Due to the different coordination geometry of these metal ions differences may arise; in the case of the wild type prion protein fragments the metal binding preference was different; it shows a significant preference for Ni(II) binding at His residue (which is completely opposite to those reported for Cu(II) ion) It can be explained by the effect of the side chains, while nickel(II) ions form planar species where the shorter side chains are present, copper(II) ions are stabilized by axial interactions. Smaller fragments of the tridecapeptide (Ac-PH85AAA-NH2 and AcPH85AAAGTH96S-NH2) were synthesized and studied for comparison
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