The cellular form of the prion protein, PrPc, is critically required for the establishment of prion diseases, such as Creutzfeldt–Jakob disease. Within the N-terminal half of PrPc are four octapeptide repeats that bind Cu2+. Exposure of neuronal cells expressing PrPc to Cu2+ results in the rapid endocytosis of the protein. First, PrPc 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 PrPc 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 PrPc. Zn2+ also promotes the endocytosis of PrPc, a phenomenon that is also dependent on the octapeptide repeats and requires LRP1.

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