The dimeric and tetrameric octarepeat fragments of prion protein behave differently to its monomeric unit

Abstract

Potentiometric and spectroscopic data have shown that octarepeat dimer and tetramer are much more effective ligands for Cu(II) ions than simple octapeptide. Thus, the whole N-terminal segment of prion protein due to cooperative effects, could be more effective in binding of Cu(II) than simple peptides containing a His residue. The gain of the Cu(II) binding by longer octarepeat peptides derives from the involvement of up to four imidazoles in the coordination of the first Cu(II) ion. This type of binding increases the order of the peptide structure, which allows successive metal ions for easier coordination.

Binary and ternary mixed metal complexes of terminally free peptides containing two different histidyl binding sites

“…Moreover, the formation of polynuclear copper(II) and/or nickel(II) complexes was observed with various multihistidine peptides [8][9][10][11]. Peptide fragments of prion protein and amyloid-β peptides provided the most evident examples for the binding of more than one copper(II) and nickel(II) ions in these complexes [12][13][14][15][16]. It was also clear from these studies that the metal ion affinities of the various histidyl sites are not equivalent and a series of coordination isomers of the mononuclear complexes can be present in solution [5,16].…”

The Octarepeat Domain of the Prion Protein Binds Cu(II) with Three Distinct Coordination Modes at pH 7.4

“…However, at intermediate occupancy, a single Cu 2+ may be coordinated by two or more His imidazoles. 15,33,34 Although a detailed mechanism has not yet been proposed, significant changes in octarepeat organization may ultimately explain the molecular basis for the proposed binding cooperativity. 33 Alternatively, distinct binding modes as a function of copper occupancy may point to a copper sensing role for PrP C , or even a protein that carries out several different functions depending on the extracellular Cu 2+ concentration.…”

“…Valensin et al reported detailed potentiometric titrations on (PHGGGWGQ)2 and (PHGGGWGQ)4. 34 At fixed copper/peptide ratios, pH is scanned while monitoring proton release. Remarkably, these investigations reveal a wide range of distinct deprotonated species.…”

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

“…Beside the well known human serum albumin (HSA) [1], probably the prion proteins (PrP) [2] are the most studied examples of such sequences. Studies on the metal ion binding of peptides related to the N-terminal of HSA [3][4][5], and those mimicking the octarepeat region of PrP [6][7][8] demonstrated the usefulness of such studies. Besides, several peptides copying the putative metal binding sequences of e.g.…”

“…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.…”