title: COOH-terminal sequence of the cellular prion protein directs subcellular trafficking and controls conversion into the scrapie isoform.
abstract: Efficient formation of scrapie isoform of prion protein (PrP(Sc)) requires targeting PrP(Sc) by glycophosphatidyl inositol (GPI) anchors to caveolae-like domains (CLDs). Redirecting the cellular isoform of prion protein (PrP(C)) to clathrin-coated pits by creating chimeric PrP molecules with four different COOH-terminal transmembrane domains prevented the formation of PrP(Sc). To determine if these COOH-terminal transmembrane segments prevented PrP(C) from refolding into PrP(Sc) by altering the structure of the polypeptide, we fused the 28-aa COOH termini from the Qa protein. Two COOH-terminal Qa segments differing by a single residue direct the transmembrane protein to clathrin-coated pits or the GPI form to CLDs; PrP(Sc) was formed from GPI-anchored PrP(C) but not from transmembrane PrP(C). Our findings argue that PrP(Sc) formation is restricted to a specific subcellular compartment and as such, it is likely to involve auxiliary macromolecules found within CLDs.
authors.affiliation: Department of Neurology, University of California, San Francisco 94143-0518, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kaneko
authors.forename: M
authors.initials: M
authors.lastname: Vey
authors.forename: M
authors.initials: M
authors.lastname: Scott
authors.forename: S
authors.initials: S
authors.lastname: Pilkuhn
authors.forename: F E
authors.initials: FE
authors.lastname: Cohen
authors.forename: S B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D000818:Animals; D001483:Base Sequence; D002999:Clone Cells; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009447:Neuroblastoma; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments / Q000302:isolation & purification / Q000378:metabolism; D017354:Point Mutation; D011328:Prions / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000302:isolation & purification / Q000378:metabolism; D012608:Scrapie / Q000503:physiopathology*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D017261:Glycosylphosphatidylinositols; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D011328:Prions; D011993:Recombinant Fusion Proteins