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 Pro 85 to Pro 96 (human sequence numbering, corresponding to Pro 82 to Pro 93 in the mouse). There have been several, contradictory predictions of secondary structure in this region; either ␤-sheet, ␣-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 ␣-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 ␣-helix, penetrating up to 12 Å into the bilayer. The ␣-helix is tilted ϳ9°, and the central lysine is in an ideal snorkeling position for side-chain interaction with the negatively charged phospholipid head groups.Multiple sclerosis (MS) 1 is thought to be an autoimmune disease characterized by chronic inflammatory response against myelin in the central nervous system. There is significant evidence that myelin basic protein (MBP) is a candidate antigen for T-cells and autoantibodies in MS (1). The 18.5-kDa isoform of MBP maintains the compaction of the myelin sheath in the central nervous system by anchoring the cytoplasmic face of the two apposing bilayers (2, 3). The mechanism and sites that are important for membrane adhesion are not known.The level of anti-MBP antibodies is increased in the cerebrospinal fluid of patients with active MS (4), as well as in 96% of patients with relapsing and chronic MS (5). An MBP region between Pro 85 and Pro 96 (human sequence numbering) was identified to be a minimal B cell epitope and a T cell epitope for HLA DR2b (DRB1*1501)-restricted T cells that recognize the protein (1, 6). This epitope overlaps with the DR2a-restricted epitope for T-cells reactive to MBP residues 87-106 (7). Experimental treatments for MS based on peptide mimetics of MBP have focused on this region of the protein (8).In solution, MBP is "intrinsically unstructured" (or "natively unfolded") (9). Upon binding to detergents or lipids, the levels of ␤-sheet and especially ␣-helical structure increase dramatically (10, 11). Presently the tertiary structure of MBP is unknown, with the most detailed predictions coming from Martenson (12) and Stoner (13) in the mid-1980s. In these models, as well as in a newer model based upon further research on an electron microscopy single-particle reconstruction, residues 86 -92 are found in a ␤-sheet (14, 15). Using [ 1 H]NMR and circular dichroic spectropolarimetry of various MBP peptides with detergent micelles, Mendz et al. (16) suggested that there were discrete interaction sites in the protein, one of which could be a helix between residues 87 and 97. Based on the arrangement of hydrophobic and hydrophilic residues, Warren et al. (6) predicted that this epitope of MBP was an amphipathic ␣-helix located at the interface between the oligodendrocyte cytoplasm and the me...

The Essential Environmental Cause of Multiple Sclerosis Disease

“…In the recent years, researchers, national and international organizations have focused on the disorder of the immune system [1], genetics [2][3][4] and environmental factors [5,6]. Most of researchers found that the high intake of vitamin D is associated with lower prevalence rates of multiple sclerosis [7].…”

Structural Transition in Myelin Membrane as Initiator of Multiple Sclerosis

“…9,10 When bound to a lipid surface, secondary structural elements form, and the hydrophobic parts of the protein are embedded in the bilayer. 11,12 Moreover, the bound MBP has been shown to adopt a compact "C" shape, 13 and to associate with neighboring MBPs to create a mesh-like structure within the cytoplasmic space. 3 Both the topology of the bound MBP structure and the supramolecular organization of the MBP network have been studied extensively with large uncertainties.…”

Interaction forces and adhesion of supported myelin lipid bilayers modulated by myelin basic protein

“…Physical-chemical studies of the interaction of MBP with myelin lipids have confirmed that the attraction between MBP and lipid is largely electrostatic (15): There are Ϸ20 Ϯ 3 anionic lipid molecules per molecule of MBP in healthy myelin (15). In addition, there is good evidence that the hydrophobic segments that make up Ϸ25% of MBP (3,15) interact with the hydrophobic lipid chains either by partially penetrating into the bilayers (16) or by expanding the bilayers (14,15). These lipid-protein interactions also affect the intramembrane forces that determine the fluidity and mobility of the lipids and proteins within the membranes (3) and the formation of compositionally distinct domains (17).…”