FIG. 3.

Structural features and redox properties of relevant metal-protein complexes in neurodegenerative diseases. (a) Cu can interact with PrP^C, Aβ, and α-synuclein. PrP^C has three coordination sites: histidine (His) His96, His111, and an octarepeat. Cu²⁺ coordination to His96 and His111 yields very similar complexes different to those generated upon Cu⁺ binding to His111. The octarepeat region coordinates up to four Cu²⁺ ions depending on the Cu²⁺/PrP^C stoichiometric ratio. At low Cu:protein ratios, four His residues coordinate Cu²⁺, while at high ratios each His can bind one Cu²⁺ ion. The different coordination chemistry of these Cu-PrP^C complexes is reflected in their redox properties. Similarly, Cu²⁺ coordination to Aβ (1–40/42) yields two different coordination modes that display different redox properties. Recently, coordination to Aβ (4–40/42) has also been described; this site displays higher affinity for Cu²⁺ than Aβ (1–40/42), and it yields a redox silent complex. On the contrary, nonacetylated α-synuclein has two high-affinity binding sites for Cu²⁺: site one involving residues at the N-terminal, and site two at His50. Acetylation of α-synuclein, as described to occur in vivo, abolishes Cu²⁺ binding at site 1, although both forms of α-synuclein can bind Cu⁺. (b) Fe²⁺ can interact with Aβ, but the redox properties of Fe-Aβ complexes remain unclear. Interestingly, recent studies propose that heme can bind to Aβ, yielding a heme (Fe)-Aβ complex with peroxidase activity. (c) Finally, Zn²⁺ can bind to the octarepeat region of PrP^C and with Aβ. Cu²⁺, cupric ion; Fe, iron; Fe²⁺, ferrous; Zn, zinc.