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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Conference Article|
November 19 2008
Mechanism of the metal-mediated endocytosis of the prion protein
Nigel M. Hooper;
Nigel M. Hooper
1
1Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, U.K., and Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, U.K.
1To whom correspondence should be addressed (email n.m.hooper@leeds.ac.uk).
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David R. Taylor;
David R. Taylor
1Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, U.K., and Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, U.K.
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Nicole T. Watt
Nicole T. Watt
1Proteolysis Research Group, Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, U.K., and Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, U.K.
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Publisher: Portland Press Ltd
Received:
June 05 2008
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem Soc Trans (2008) 36 (6): 1272–1276.
Article history
Received:
June 05 2008
Citation
Nigel M. Hooper, David R. Taylor, Nicole T. Watt; Mechanism of the metal-mediated endocytosis of the prion protein. Biochem Soc Trans 1 December 2008; 36 (6): 1272–1276. doi: https://doi.org/10.1042/BST0361272
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