title: Residues surrounding the glycosylphosphatidylinositol anchor attachment site of PrP modulate prion infection: insight from the resistance of rabbits to prion disease.
abstract: Prion diseases are a group of transmissible, invariably fatal neurodegenerative diseases that affect both humans and animals. According to the protein-only hypothesis, the infectious agent is a prion (proteinaceous infectious particle) that is composed primarily of PrP(Sc), the disease-associated isoform of the cellular prion protein, PrP. PrP(Sc) arises from the conformational change of the normal, glycosylphosphatidylinositol (GPI)-anchored protein, PrP(C). The mechanism by which this process occurs, however, remains enigmatic. Rabbits are one of a small number of mammalian species reported to be resistant to prion infection. Sequence analysis of rabbit PrP revealed that its C-terminal amino acids differ from those of PrP from other mammals and may affect the anchoring of rabbit PrP through its GPI anchor. Using a cell culture model, this study investigated the effect of the rabbit PrP-specific C-terminal amino acids on the addition of the GPI anchor to PrP(C), PrP(C) localization, and PrP(Sc) formation. The incorporation of rabbit-specific C-terminal PrP residues into mouse PrP did not affect the addition of a GPI anchor or the localization of PrP. However, these residues did inhibit PrP(Sc) formation, suggesting that these rabbit-specific residues interfere with a C-terminal PrP(Sc) interaction site.
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Nisbet
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Harrison
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Lawson
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Hill
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D007113:Immunity, Innate; D051379:Mice; D008969:Molecular Sequence Data; D011257:Pregnancy Proteins / Q000235:genetics* / Q000378:metabolism*; D017096:Prion Diseases; D011485:Protein Binding; D011817:Rabbits; D016415:Sequence Alignment
chemical_list: D017261:Glycosylphosphatidylinositols; C057074:Plfr protein, mouse; D011257:Pregnancy Proteins