Effects of the pathological Q212P mutation on human prion protein non-octarepeat copper binding site

Prion diseases or transmissible spongiform encephalopathies (TSEs) are a class of fatal neurodegenerative disorders char- acterized by the spongy appearance of brain tissue, synaptic degeneration, microglia and astrocytes activation, neuronal loss and altered redox control. TSEs can be sporadic, iatrogenic and genetic maladies. The etiological agent is a misfolded form, PrPSc or prion, of the cellular prion protein, called PrPC. PrPC inter- acts 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 well as the role of transition metals on the conversion. Many efforts have been made to highlight the effect of pathological point mutations on PrP tertiary structure. Since TSEs present metal dys-homeostasis and increased oxidative stress, we described the copper-binding site located in the human globular domain of PrP—HuPrP(90– 231)—carrying the pathological mutation Q212P. This mutation is responsible for a GSS syndrome and represents a unique case in prion structural biology in which a mutation induces remark- able structural differences. We used synchrotron-based X-ray absorption fine structure (XAFS) technique to study Cu(II) and Cu(I) coordination geometries in the mutant, and compared them with that obtained using the wild-type protein. By ana- lyzing extended X-ray absorption fine structure (EXAFS) and X-ray absorption near-edge structure (XANES), we highlighted changes in copper coordination induced by the point mutation Q212P, in both oxidative states. These changes probably cause alterations in copper homeostasis and, therefore, in redox control.