An immunodominant epitope of myelin basic protein is an amphipathic α-helix

Myelin basic protein (MBP) is a candidate autoantigen in multiple sclerosis (MS). Its dominant antigenic epitope for both B cells and T cells is residues 85–96 (human sequence). Contradictory predictions of secondary structure in this region have been made. We used molecular dynamics and site-directed cysteine-specific spin labeling to show that this segment forms a transient amphipathic a-helix, which is stabilized in 30% trifluoroethanol and on binding to a myelin-like lipid surface. When bound to the membrane, the a- helix is partially embedded in the lipid bilayer and tilted at an angle of 9°. Key contact points for antibody recognition, the two phenylalanines at positions 89–90 and lysine 91, are embedded in the bilayer and thus would be sequestered from antibody. The central lysine 91 is positioned so that its positively charged side chain protrudes out of the bilayer into the polar head group region to interact with the polar lipid head groups. Antibody binding to this epitope of membrane-bound MBP would occur only if this region transiently dissociates from the membrane. This is more likely to occur for the deiminated charge isomer of MBP (C8), which is increased in MS myelin, than for the most positively charged form (C1), since deimination of six arginines of MBP caused dissociation of the C-terminal end of MBP from the bilayer. Acknowledgment: This work was supported by grants from CIHR, NSERC, the MS Society of Canada, and the US Public Health Service