Deimination of membrane-bound myelin basic protein in multiple sclerosis exposes an immunodominant epitope.
Musse, A.A., Boggs, J.M., and Harauz, G. Proc. Nat. Acad. Sci.,103, 4422-4427 (March 21, 2006).
The severity of multiple sclerosis is highly correlated with the loss of arginine via deimination of myelin basic protein (MBP). Eight charge variants of this membrane-bound protein have been identified, and two recombinant forms, the most and least cationic (C1 and C8, respectively), form the basis of this study. Using site-directed spin labeling and EPR spectroscopy, the authors compared the membrane-bound conformational states of the two charge variants. The data indicate that the least cationic form, C8, has a shorter alpha helix than the C1 isomer, and that its alpha helix is more exposed to the lipid-aqueous interface. As a result, the C8 variant is more susceptible to proteolysis. Release of antigenic peptides following attack on this isomer by myelin-associated proteases may trigger and sustain the immune response related to the disease.
The results support the theory that although multiple sclerosis has an autoimmune component, the underlying cause of the disease may reside in an abnormal posttranslational modification of MBP through deimination.
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