New Model for Crystalline Polyglutamine Assemblies and Their Connection with Amyloid Fibrils

Abstract

Based on the interpretation of X-ray diffraction data reported for crystals of the poly-l-glutamine-rich 19-peptide D₂Q₁₅K₂, Perutz et al. (Proc. Natl. Acad. Sci. USA2002, 99, 5591−5595) proposed that hollow, water-filled nanotubes are the basic structural motif of amyloid fibers. We are able to offer an alternative interpretation for the same X-ray diffraction data. Our proposed structure consists of β-sheets, limited in size in the chain direction that stack at an intersheet distance of 0.83 nm to form cross-β crystallites. The β-sheets are composed of individual D₂Q₁₅K₂ molecules hydrogen bonding together in the a direction. The relatively linear interchain amide hydrogen bonds in this growth direction occur at two sites: (i) between neighboring backbone amides and (ii) between adjacent (glutamine) side chain amides decorating both surfaces of the β sheet. The polyQ sub-lattice unit cell is orthorhombic with parameters a =0.950 nm, b = 1.660 nm, and c = 0.695 nm; contains two β-sheet segments; and has a calculated density of 1.54 g cm^-3. A key ingredient in the proposed structure is the locking of the Q side chains by hydrogen bonding, which allow high-density packing. In addition, there is evidence suggesting that the D₂Q₁₅K₂ molecules adopt a once-folded hairpin conformation.