Deimination exposes an immunodominant epitope of membrane‐associated myelin basic protein

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Multiple sclerosis (MS) is characterized by the active degradation of myelin in the central nervous system (CNS). The resultant lesions contain T cells, B cells, and macrophages that are reactive against myelin antigens. Myelin basic protein (MBP) is one of the candidate autoantigens. The primary role of MBP in the CNS is the maintenance of myelin compaction, serving as an adhesive molecule that brings together the apposing faces of the cytoplasmic leaflet of the myelin membrane. Deimination (conversion of arginine to citrulline) of MBP reduces the net positive charge of the protein and diminishes its interactions with the membrane. Moreover, the deiminated isoform is increased both in MS adult myelin and in developing normal myelin. We have studied the effect of deimination on the conformation and membrane-association of the primary immunodominant epitope of murine MBP, V83-T92, using site-directed Cys-substitution and spin labeling, EPR spectroscopy, and site-specific proteolysis, of modified and unmodified membrane-bound MBP variants. We show that arginine loss by quasi-deimination (R→Q), at conserved deimination sites, causes the immunodominant epitope to form a more highly surface-exposed and shorter amphipathic alpha-helix. Moreover, cathepsin D digested the membrane-associated modified MBP variant 3-fold faster than the unmodified form that is predominant in healthy myelin. These results suggest a mechanism for myelin degradation and autoimmune pathogenesis in MS.