Copper, zinc and iron in neurodegenerative diseases (Alzheimer's, Parkinson's and prion diseases)

The basic role of metal ions including copper, zinc and iron in neurological pathologies is generally accepted. The relationship between the development of disease and particular metal ions are very complicated and complex. Thus, comprehension of metal homeostasis, details of transport and interactions with biomolecules is essential for understanding of normal and pathological processes occurring in the living system. Homeostasis of metal ions usually involve huge set of proteins which regulate the proper metal biology. Disorder in metal homeostasis may result in serious pathologies including neurodegenerative diseases. Metals ions, especially copper, zinc and iron play very important roles in neurodegeneration having impact on both protein structure (misfolding) and oxidative stress. Metal ion binding to proteins involved in neurodegeneration is therefore an important factor for whole brain damage processes. All these aspects are discussed in the review

Copper-induced structural propensities of the amyloidogenic region of human prion protein

Transmissible spongiform encephalopathies are associated with the misfolding of the cellular Prion Protein (PrPC) to an abnormal protein isoform, called scrapie prion protein (PrPSc). The structural rearrangement of the fragment of N-terminal domain of the protein spanning residues 91–127 is critical for the observed structural transition. The amyloidogenic domain of the protein encloses two copper-binding sites corresponding to His-96 and His-111 residues that act as anchors for metal ion binding. Previous studies have shown that Cu(II) sequestration by both sites may modulate the peptide’s tendency to aggregation as it inflicts the hairpin-like structure that stabilizes the transition states leading to b-sheet formation. On the other hand, since both His sites differ in their ability to Cu(II) sequestration, with His-111 as a preferred binding site, we found it interesting to test the role of Cu(II) coordination to this single site on the structural properties of amyloidogenic domain. The obtained results reveal that copper binding to His-111 site imposes precise backbone bending and weakens the natural tendency of apo peptide to b-sheet formation

The possible role of Gly residues in prion octarepeat region in coordination of Cu2+ ions

Spectroscopic and potentiometric data have shown that insertion of tripeptides other than the Gly3 peptide fragment, Ala3 or Lys3, into the prion octarepeat region destabilizes the biologically relevant Cu2+ complex with the metal ion bound equatorially through the {Nimid,2N-} donor set. The other likely role of the high glycine content could be enforcement of the high flexibility of the N-terminal prion region resulting in the unstructured protein organization. However, the insertion of bulkier amino acid residues does not change the basic coordination mode at physiological pH which involves imidazole nitrogen and two amide nitrogen donors from the third and fourth residues