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Volume 17, Number 1, Issue of January 1, 1997 pp. 181-189
Copyright ©1997 Society for Neuroscience

Conservation of Topology, But Not Conformation, of the Proteolipid Proteins of the Myelin Sheath

Received Sept. 9, 1996; accepted Oct. 10, 1996.

Alexander Gow¹, Alexander Gragerov¹, Anthony Gard², David R. Colman¹, and Robert A. Lazzarini¹

¹ Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029-6574, and ² Department of Structural and Cell Biology, University of South Alabama College of Medicine, Mobile, Alabama 36688

The proteolipid protein gene products DM-20 and PLP are adhesive intrinsic membrane proteins that make up 50% of the protein in myelin and serve to stabilize compact myelin sheaths at the extracellular surfaces of apposed membrane lamellae. To identify which domains of DM-20 and PLP are positioned topologically in the extracellular space to participate in adhesion, we engineered N-glycosylation consensus sites into the hydrophilic segments and determined the extent of glycosylation. In addition, we assessed the presence of two translocation stop-transfer signals and, finally, mapped the extracellular and cytoplasmic dispositions of four antibody epitopes. We find that the topologies of DM-20 and PLP are identical, with both proteins possessing four transmembrane domains and N and C termini exposed to the cytoplasm. Consistent with this notion, DM-20 and PLP contain within their N- and C-terminal halves independent stop-transfer signals for insertion into the bilayer of the rough endoplasmic reticulum during de novo synthesis. Surprisingly, the conformation (as opposed to topology) of DM-20 and PLP may differ, which has been inferred from the divergent effects that many missense mutations have on the intracellular trafficking of these two isoforms. The 35 amino acid cytoplasmic peptide in PLP, which distinguishes this protein from DM-20, imparts a sensitivity to mutations in extracellular domains. This peptide may normally function during myelinogenesis to detect conformational changes originating across the bilayer from extracellular PLP interactions in trans and trigger intracellular events such as membrane compaction in the cytoplasmic compartment.

Key words: protein topology; protein conformation; protein misfolding; proteolipid protein; PLP; DM-20; 1A9 monoclonal antibody; O10 monoclonal antibody; myelin; missense mutations; transfection; central nervous system; evolution; transmembrane signaling

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