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 Cu(2+). Exposure of neuronal cells expressing PrP(c) to Cu(2+) 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). Zn(2+) also promotes the endocytosis of PrP(c), a phenomenon that is also dependent on the octapeptide repeats and requires LRP1.
Hooper
Nigel M
NM
Faculty of Biological Sciences, Proteolysis Research Group, Institute of Molecular and Cellular Biology, University of Leeds, Leeds, UK. n.m.hooper@leeds.ac.uk
Taylor
David R
DR
Watt
Nicole T
NT
D000818:Animals; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D008670:Metals / Q000378:metabolism*; D018621:PrPC Proteins / Q000378:metabolism*
D002966:Clathrin; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008670:Metals; D018621:PrPC Proteins