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J. Biol. Chem., Vol. 279, Issue 9, 7530-7536, February 27, 2004

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The Membrane Domains Occupied by Glycosylphosphatidylinositol-anchored Prion Protein and Thy-1 Differ in Lipid Composition^*

Britta Brügger, Catriona Graham¶, Iris Leibrecht, Enrico Mombelli¶, Angela Jen¶, Felix Wieland, and Roger Morris¶||

From the Biochemie-Zentrum Heidelberg (BZH) Ruprecht-Karls-Universität, Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany and the ^¶Molecular Neurobiology Group, MRC Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom

Glycosylphosphatidylinositol-anchored prion protein and Thy-1, found in adjacent microdomains or "rafts" on the neuronal surface, traffic very differently and show distinctive differences in their resistance to detergent solubilization. Monovalent immunogold labeling showed that the two proteins were largely clustered in separate domains on the neuronal surface: 86% of prion protein was clustered in domains containing no Thy-1, although 40% of Thy-1 had a few molecules of prion protein associated with it. Only 1% of all clusters contained appreciable levels of both proteins (3 immunogold label for both). In keeping with this distribution, immunoaffinity isolation of detergent-resistant membranes (DRMs) using the non-ionic detergent Brij 96 yielded prion protein DRMs with little Thy-1, whereas Thy-1 DRMs contained 20% of prion protein. The lipid content of prion protein and Thy-1 DRMs was measured by quantitative nano-electrospray ionization tandem mass spectrometry. In four independent preparations, the lipid content was highly reproducible, with Thy-1 and prion protein DRMs differing markedly from each other and from the total DRM pool from which they were immunoprecipitated. Prion protein DRMs contained significantly more unsaturated, longer chain lipids than Thy-1 DRMs and had 5-fold higher levels of hexosylceramide. The different lipid compositions are in keeping with the different trafficking dynamics and solubility of the two proteins and show that, under the conditions used, DRMs can isolate individual membrane microenvironments. These results further identify unsaturation and glycosylation of lipids as major sources of diversity of raft structure.

Received for publication, September 15, 2003 , and in revised form, November 20, 2003.

^* This work was supported by European Union Grant HPRN-CT-2000-00077 and MRC Grant G0000839 (to R. M.) and Deutsche Forschungsgemeinschaft Grants SFB352, C6 and Z3, and Grant Wi654/7-1 (to F. W. and B. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplementary tables.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Molecular Neurobiology Group, MRC Centre for Developmental Neurobiology, King's College London, Guy's Campus, London SE1 1UL, UK. Tel.: 44-207-848-6801; Fax: 44-207-848-6816; E-mail: roger.morris{at}kcl.ac.uk.

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