Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 278, Issue 39, Pages 37241-37248Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M302036200
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The association of the prion protein (PrP) with sphingolipid- and cholesterol-rich lipid rafts is instrumental in the pathogenesis of the neurodegenerative prion diseases. Although the glycosylphosphatidylinositol (GPI) anchor is an exoplasmic determinant of raft association, PrP remained raft-associated in human neuronal cells even when the GPI anchor was deleted or substituted for a transmembrane anchor indicating that the ectodomain contains a raft localization signal. The raft association of transmembrane-anchored PrP occurred independently of Cu(II) binding as it failed to be abolished by either deletion of the octapeptide repeat region ( residues 51 - 90) or treatment of cells with a Cu( II) chelator. Raft association of transmembrane-anchored PrP was only abolished by the deletion of the N-terminal region ( residues 23 - 90) of the ectodomain. This region was sufficient to confer raft localization when fused to the N terminus of a non-raft transmembrane-anchored protein and suppressed the clathrin-coated pit localization signal in the cytoplasmic domain of the amyloid precursor protein. These data indicate that the N-terminal region of PrP acts as a cellular raft targeting determinant and that residues 23 - 90 of PrP represent the first proteinaceous raft targeting signal within the ectodomain of a GPI-anchored protein.
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