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J. Biol. Chem., Vol. 278, Issue 39, 37241-37248, September 26, 2003

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The N-terminal Region of the Prion Protein Ectodomain Contains a Lipid Raft Targeting Determinant^*

Adrian R. Walmsley , Fanning Zeng  and Nigel M. Hooper ¶

From the School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom

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.

Received for publication, February 26, 2003 , and in revised form, July 5, 2003.

^* This work was supported by Strategic Project Grants from the Medical Research Council of Great Britain. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Novartis Pharma Research, Basel, Switzerland.

Recipient of an Overseas Research Scholarship and a University of Leeds Tetley and Lupton Scholarship.

^¶ To whom correspondence should be addressed. Tel.: 44-113-343-3163; Fax: 44-113-343-3167; E-mail: n.m.hooper{at}leeds.ac.uk.

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