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Abstract

Using solution NMR spectroscopy, three-dimensional structures have been obtained for an 18-residue synthetic polypeptide fragment of 18.5 kDa myelin basic protein (MBP, human residues Q81–T98) under three conditions emulating the protein's natural environment in the myelin membrane to varying degrees: (a) an aqueous solution (100 mm KCl pH 6.5), (b) a mixture of trifluoroethanol (TFE-d₂) and water (30 : 70% v/v), and (c) a dispersion of 100 mm dodecylphosphocholine (DPC-d₃₈, 1 : 100 protein/lipid molar ratio) micelles. This polypeptide sequence is highly conserved in MBP from mammals, amphibians, and birds, and comprises a major immunodominant epitope (human residues N83–T92) in the autoimmune disease multiple sclerosis. In the polypeptide fragment, this epitope forms a stable, amphipathic, α helix under organic and membrane-mimetic conditions, but has only a partially helical conformation in aqueous solution. These results are consistent with recent molecular dynamics simulations that showed this segment to have a propensity to form a transient α helix in aqueous solution, and with electron paramagnetic resonance (EPR) experiments that suggested a α-helical structure when bound to a membrane [I. R. Bates, J. B. Feix, J. M. Boggs & G. Harauz (2004) J Biol Chem, 279, 5757–5764]. The high sensitivity of the epitope structure to its environment is characteristic of intrinsically unstructured proteins, like MBP, and reflects its association with diverse ligands such as lipids and other proteins.