is speculated to be an elusive ligand-protein, but, so far, no such compound has been identified. However, a large body of research has developed on candidates and their interaction with the PrPC. Copper, zinc, manganese, and nickel are confirmed PrP ligands that bind to its octarepeat region. Ligand binding causes a conformational change with unknown effect. Heavy metal binding at PrP has been linked to resistance to oxidative stress arising from heavy metal toxicity. PrPC (normal cellular) isoform Although the precise function of PrP is not yet known, it is possibly involved in the transport of ionic copper to cells from the surrounding environment. Researchers have also proposed roles for PrP in cell signaling or in the formation of synapses. PrPC attaches to the outer surface of the cell membrane by a glycosylphosphatidylinositol anchor at its C-terminal Ser231. Prion protein contains five octapeptide repeats with sequence PHGGGWGQ (though the first repeat has the slightly-modified, histidine-deficient sequence PQGGGGWGQ). This is thought to generate a copper-binding domain via nitrogen atoms in the histidine imidazole side-chains and deprotonated amide nitrogens from the 2nd and 3rd glycines in the repeat. The ability to bind copper is, therefore, pH-dependent. NMR shows copper binding results in a conformational change at the N-terminus. PrPSc (scrapie) isoform PrPSc is a conformational isoform of PrPC, but this orientation tends to accumulate in compact, protease-resistant aggregates within neural tissue. The abnormal PrPSc isoform has a different secondary and tertiary structure from PrPC, but identical primary sequence. Circular dichroism shows that normal PrPC has 42% alpha helical and 3% beta sheet content, whereas PrPSc is only 30% alpha helix and 43% beta sheet. However, the presence of alpha helices in infectious PrPSc has come into question, with current models proposing a lack of alpha helices altogether, replaced instead with a total beta sheet composition. This refolding renders the PrPSc isoform extremely resistant to proteolysis. The propagation of PrPSc is a topic of great interest, as its accumulation is a pathological cause of neurodegeneration. Based on the progressive nature of spongiform encephalopathies, the predominant hypothesis posits that the change from normal PrPC is caused by the presence and interaction with PrPSc. Strong support for this is taken from studies in which PRNP-knockout mice are resistant to the introduction of PrPSc. Despite widespread acceptance of the conformation conversion hypothesis, some studies mitigate claims for a direct link between PrPSc and cytotoxicity. Polymorphisms at