Redox Behaviour of Copper-bound Prion Protein

The prion protein (PrP) is a cell-surface protein which has the potential to cause mammalian neurodegenerative diseases, including Creutzfeldt-Jakob disease in humans and scrapie in sheep. Although it is ubiquitously expressed in mammals, birds and reptiles, it predominates at the presynaptic membrane of the central nervous system. The physiological function of PrP is a matter of great debate, and it has been implicated in a multitude of processes. An area of intense interest is the ability of the N-terminal domain of the protein to bind copper ions with high specificity and affinity. A popular suggestion for the protein, connected with its Cu(II)-binding ability, is that of potential antioxidant, and in particular superoxide dismutase (SOD)-like, activity. To carry out this role, the metal ion is required to redox-cycle between the +1 and +2 oxidation states. It is also thought that PrP may be important for Cu(I) uptake following synaptic depolarisation and copper release. Limited understanding of the interaction of reduced copper with the protein triggered the research undertaken for this thesis. It was discovered that the amyloidogenic region of the protein binds Cu(I) with relatively high affinity (Kd ~10-12 – 10-15 M) through a (His)2(Met)2 coordination site. This site possesses quasi-reversible redox chemistry, but large structural rearrangement is expected to be required in order for redox-cycling to occur. Correspondingly, a direct assay for SOD activity showed negligible activity compared with native Cu,Zn-SOD. Cu(II) bound to an oligopeptide corresponding to a portion of the amyloidogenic region was able to undergo oxidation to the trivalent state, potentially signifying non-SOD antioxidant activity. The physiological relevance of the interaction between PrP and Cu(I) remains elusive. The leading conclusion, from comparison of the proposed Cu(I) site with similar sites, is that the protein may act as a Cu(I) transporter within the anaerobic synaptic space