Prion diseases are a class of fatal
neurodegenerative disorders characterized by brain spongiosis, synaptic degeneration, microglia and astrocytes activation, neuronal loss and altered redox control. These maladies can be sporadic, iatrogenic and genetic. The etiological agent is the
prion, a misfolded form of the cellular
prion protein, PrP(C). PrP(C) interacts with
metal ions, in particular
copper and
zinc, through the octarepeat and non-octarepeat binding sites. The physiological implication of this interaction is still unclear, as is the role of metals in the conversion. Since
prion diseases present
metal dyshomeostasis and increased oxidative stress, we described the
copper-binding site located in the human C-terminal domain of PrP-HuPrP(90-231), both in the wild-type
protein and in the
protein carrying the pathological mutation Q212P. We used the
synchrotron-based X-ray absorption fine structure technique to study the Cu(II) and Cu(I) coordination geometries in the mutant, and we compared them with those obtained using the wild-type
protein. By analyzing the extended X-ray absorption fine structure and the X-ray absorption near-edge structure, we highlighted changes in
copper coordination induced by the point mutation Q212P in both oxidation states. While in the wild-type
protein the
copper-binding site has the same structure for both Cu(II) and Cu(I), in the mutant the coordination site changes drastically from the oxidized to the reduced form of the
copper ion.
Copper-binding sites in the mutant resemble those obtained using
peptides, confirming the loss of short- and long-range interactions. These changes probably cause alterations in
copper homeostasis and, consequently, in redox control.