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GLYCOSYLATION AND GPI ANCHORAGE OF THE PRION PROTEIN
N. M. Hooper
School of Biochemistry and Microbiology Leeds Institute for Genetics
Health and Therapeutics University of Leeds, Leeds, UK
Prion diseases or transmissible spongiform encephalopathies are a group of neurod- egenerative disorders including scrapie in sheep, bovine spongiform encephalopathy in cattle, Creutzfeldt–Jakob disease and Gerstmann–Straussler–Scheinker disease in humans. In prion diseases the normal cellular form of the prion protein (PrPC) undergoes a conformational conversion to the b-sheet-rich scrapie isoform (PrPSc).
Although PrPC is critical for the development of prion disease through its conversion into PrPSc, the physiological role of PrPC is less clear. PrPC undergoes a variety of post-translational processing events, including glycosylation, GPI anchorage and
Figure 1.
95 John S. Axford (ed.), Glycobiology and Medicine, 95-96.
© 2005 Springer. Printed in the Netherlands.
96 N. M. Hooper
proteolysis. PrP contains two N-glycosylation sequons at Asn180 and Asn196, both of which can be glycosylated. However, either one or both of the acceptor Asn may remain unglycosylated, giving rise to unglycosylated, mono-glycosylated and di-glycosylated proteins. The ratio of these three glycoforms appears to be character- istic for particular ‘strains’ of PrP. N-glycosylation of PrP is dramatically influenced by its membrane topology and by the distance of the Asn sequons to the C-terminus of the protein. The role of these post-translational modifications in the life cycle of PrPC will be discussed. The C-terminal signal peptide directs the addition of a glycosyl-phosphatidylinositol (GPI) anchor to the protein within the lumen of the ER. This GPI anchor, along with a determinant in the N-terminal region of the protein, promotes the association of PrPC with cholesterol-rich lipid rafts that are involved in the trafficking of the protein and its conversion to PrPSc.
REFERENCES
1. Walmsley, A. R., Zeng, F. and Hooper, N. M. (2001). Membrane topology influences N-glycosylation of the prion protein. EMBO J.20, 703–712.
2. Walmsley, A. R. and Hooper, N. M. (2003). Distance of sequons to the C-terminus influences the cellular N-glycosylation of the prion protein. Biochem. J. 370, 351–355.
3. Walmsley, A. R., Zeng, F. and Hooper, N. M. (2003). The N-terminal region of the prion protein ectodomain contains a lipid raft targeting determinant. J. Biol. Chem. 278, 37241–37248.
