Mechanism of the metal-mediated endocytosis of the prion protein

The cellular form of the prion protein, PrP^c, is critically required for the establishment of prion diseases, such as Creutzfeldt–Jakob disease. Within the N-terminal half of PrP^c are four octapeptide repeats that bind Cu²⁺. Exposure of neuronal cells expressing PrP^c to Cu²⁺ results in the rapid endocytosis of the protein. First, PrP^c translocates laterally out of detergent-resistant lipid rafts into detergent-soluble regions of the plasma membrane, then it is internalized through clathrin-coated pits. The extreme N-terminal region of PrP^c is critically required for its endocytosis, as is the transmembrane LRP1 (low-density lipoprotein receptor-related protein-1). Incubation of cells with a competitive inhibitor of LRP1 ligands, receptor-associated protein, or down-regulation of LRP1 with siRNA (short interfering RNA) reduces the endocytosis of PrP^c. Zn²⁺ also promotes the endocytosis of PrP^c, a phenomenon that is also dependent on the octapeptide repeats and requires LRP1.