MEMBRANE TOPOLOGY OF THE MYELIN/OLIGODENDROCYTE GLYCOPROTEIN

Myelin/oligodendrocyte glycoprotein (MOG), a specific component of the mammalian central nervoussystem, is located on the surface of the oligodendrocyte plasma membrane and the outermost lamellae ofmature myelin; it is expressed during the latter steps of myelinogenesis. It has been shown that MOG mayplay a pathological role in autoimmune demyelinating diseases of the central nervous system, although itsphysiological function remains unknown. MOG is an integral membrane glycoprotein with an extracellu-lar immunoglobulin-like domain and two hydrophobic segments which were predicted to be membrane-spanning on the basis of hydropathy analysis. As a first step in elucidation of MOG function, we haveinvestigated its membrane topology, combining immunofluorescence studies on cultured oligodendrocytesand MOG-transfected Chinese hamster ovary cells with biochemical analyses, includingin vitro transla-tion, membrane insertion and protease-digestion assays. Our results indicate that the C-terminal tail ofMOG is located into the cytoplasm, and that only the first hydrophobic region of MOG spans the mem-brane whereas the second hydrophobic region appears to be semi-embedded in the lipid bilayer, lyingpartially buried in the membrane with its N-terminal and C-terminal boundaries facing the cytoplasm.Keywords: MOG; myelin; topology.Central nervous system myelin is synthesized as an exten-sion of the oligodendrocyte plasma membrane, which wrapsaround axons in a concentric multilamellar sheath. Proteolipidproteins (PLP) and myelin basic proteins (MBP) are the mostabundant components [1], accounting for about 80% of the pro-tein. Myelin also contains minor glycoprotein components, suchas myelin-associated glycoprotein (MAG) and myelin/oligoden-drocyte glycoprotein (MOG).MOG was originally identified as the antigen recognized bythe demyelinating antibodies present in serum of animals immu-nized with whole-brain homogenate [2] and was later charac-terized as a 26 kDa to 28-kDa glycoprotein [3]. Given its lateexpression during myelinogenesis in mammals [426] and itslocation at the membrane surface of oligodendrocytes and exter-nal lamellae of myelin sheaths [4, 7], MOG has been proposedto play a role either in the completion and maintenance of my-elin sheath [5, 8], or in the adhesion of adjacent myelinatedtracts [9]. However, in vivo and in vitro studies suggested thatMOG may be a target autoantigen in autoimmune demyelinatingdiseases of the central nervous system. In animals with experi-mental autoimmune encephalomyelitis, an experimental modelfor multiple sclerosis, the injection of MOG peptides can initiate