Deimination of membrane-bound myelin basic protein in multiple sclerosis exposes an immunodominant epitope.
The degradation of myelin in the CNS is the hallmark of multiple sclerosis. Reduction in the net positive charge of myelin basic protein (MBP), through deimination, correlates strongly with disease severity and may mediate myelin instability and loss of compaction. Using Cys scanning, spin labeling, EPR spectroscopy, and site-specific proteolysis, we show that in the membrane-bound state the primary immunodominant epitope, V83-T92, of the less cationic recombinant murine MBP C8 mimic (rmC8) forms a more highly surface-exposed and shorter amphipathic alpha-helix than in the unmodified form, recombinant murine MBP C1 mimic (rmC1), analogous to the most cationic and abundant isomer of MBP in normal myelin. Moreover, cathepsin D digested lipid-associated rmC8 3-fold faster than rmC1, and cleavage at F86-F87 occurred more readily in rmC8 than rmC1. These findings suggest a mechanism for initial loss of myelin stability and the autoimmune pathogenesis of multiple sclerosis.
Musse
Abdiwahab A
AA
Department of Molecular and Cellular Biology, and Biophysics Interdepartmental Group, University of Guelph, Guelph, Ontario, Canada N1G 2W1.
Boggs
Joan M
JM
Harauz
George
G
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D002402:Cathepsin D / Q000378:metabolism; D002412:Cations / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D016056:Immunodominant Epitopes / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism; D009154:Mutation; D004676:Myelin Basic Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D000089842:Xenotropic and Polytropic Retrovirus Receptor
D002412:Cations; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D011994:Recombinant Proteins; D000089842:Xenotropic and Polytropic Retrovirus Receptor; C000715268:Xpr1 protein, mouse; D002402:Cathepsin D