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First published online May 28, 2005
doi: 10.1242/10.1242/jcs.02365

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Palmitoylation is a sorting determinant for transport to the myelin membrane

¹ Department of Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler-Strausse 3, 72076 Tübingen, Germany
² Center for Biochemistry and Molecular Cell Biology, University of Göttingen, Humboldtallee 23, 37075 Göttingen, Germany
³ Institute of Pathology, Liebermeisterstr. 8, University of Tübingen, 72076 Tübingen, Germany
⁴ Max-Planck-Institute for Experimental Medicine, Hermann-Rein-Strausse 3, 37075 Göttingen, Germany
⁵ Department of Neurodegeneration and Restorative Research, Center of Neurological Medicine and CMPB, Waldweg 33, 37073 Göttingen, Germany

^* Author for correspondence (e-mail: msimons{at}gwdg.de)

Accepted 9 March 2005

Myelin is a specialized membrane enriched in glycosphingolipids and cholesterol that contains a restricted set of proteins. The mechanisms by which oligodendrocytes target myelin components to myelin are not known. To identify the sorting determinants for protein transport to myelin, we used a primary oligodendrocyte culture system in which terminal differentiation is synchronized and there is excessive deposition of myelin-like membranes (MLMs). Because several myelin proteins are palmitoylated, we explored the role of acylation in protein transport to MLMs. We found that palmitoylation-deficient mutants of a major myelin protein, proteolipid protein (PLP/DM20), were less efficiently targeted to MLMs. The N-terminal 13 amino acids of PLP/DM20, which are palmitoylated at three sites, were sufficient to direct a fluorescent fusion protein to MLMs. Mutagenesis of the N-terminal palmitoylation motif abolished the transport of the fusion protein to MLMs, indicating that palmitoylation is required for sorting to myelin. Similar results were obtained in myelinating co-cultures of oligodendrocytes and neurons. Furthermore, the combined farnesylation/palmitoylation signals from c-Ha-Ras and the N-terminal consensus sequence for dual palmitoylation from neuromodulin were sufficient for the transport of fluorescent fusion proteins to MLMs. Thus, we conclude that palmitoylation is a sorting determinant for transport to the myelin membrane.

Key words: Oligodendrocytes, Myelin, Proteolipid protein, Palmitoylation, Membrane trafficking, Sorting determinants

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