Fig. 8. Schematic showing the mechanism of internalisation of PrP^C. PrP^C is attached to the exoplasmic leaflet of the plasma membrane by its GPI anchor and localises within detergent-insoluble rafts through interactions between its N-terminal region [residues 23-90, red (Walmsley et al., 2003)] and a raft-resident protein or lipid. Upon Cu²⁺ binding to the octapeptide repeats (blue), the protein undergoes a conformational change that dissociates it from the raft-resident partner and PrP^C then moves laterally out of rafts into detergent-soluble regions of the plasma membrane. The polybasic N-terminal region then interacts with the ectodomain of a transmembrane protein that engages, via its cytoplasmic domain, with the adaptor protein AP-2 and the endocytic machinery of clathrin-coated pits.