Conformational Dimorphism and Transmembrane Orientation of Prion Protein Residues 110−136 in Bicelles

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Abstract
A fragment corresponding to the putative membrane-associating domain of the prion protein (residues 110−136) was analyzed in phospholipid bicelles. Prion(110−136) associated with bicelles and exhibited a lipid- and pH-dependent conformational dimorphism between unstructured (pH 4.5) and α-helical (pH 7.5). Mutational analysis indicated that the charge state of a single histidine residue was largely responsible for the dimorphism. Amide−lipid NOEs and amide−water chemical exchange measurements revealed that the helical conformation of prion(110−136) spanned the bilayer, and were corroborated by solid-state deuterium NMR experiments indicating that the helical axis rested at a 16° angle with respect to the bilayer normal.