An Immunodominant Epitope of Myelin Basic Protein Is an Amphipathic α-Helix

Abstract

Myelin basic protein is a candidate autoantigen in multiple sclerosis. One of its dominant antigenic epitopes is segment Pro85 to Pro 96 (human sequence numbering, corresponding to Pro82 to Pro93 in the mouse). There have been several, contradictory predictions of secondary structure in this region; either β-sheet, α-helix, random coil, or combinations thereof have all been proposed. In this paper, molecular dynamics and site-directed spin labeling in aqueous solution indicate that this segment forms a transient α-helix, which is stabilized in 30% trifluoroethanol. When bound to a myelin-like membrane surface, this antigenic segment exhibits a depth profile that is characteristic of an amphipathic α-helix, penetrating up to 12 Å into the bilayer. The α-helix is tilted ∼9°, and the central lysine is in an ideal snorkeling position for side-chain interaction with the negatively charged phospholipid head groups.