Effect of helical flanking sequences on the morphology of polyglutamine-containing fibrils.

A peptide model system has been developed to study the effects of helical flanking sequences on polyglutamine aggregation. In a companion manuscript, the kinetics of aggregation are described, comparing the influence of a well-defined heterotetrameric coiled coil to that of the helix-rich structure found in Htt(NT), a 17-residue flanking sequence found in the huntingtin protein, on polyglutamine aggregation. Here, the morphological characterization of the resultant fibrils that form for a set of peptides is reported, only one of which, KKQ25KK, has been previously studied. A careful analysis of TEM and AFM images of KKQ25KK confirms that it forms bundled fibrils of varying length and reveals, unexpectedly, that they are composed of fully extended cross-β-strands. Second, it is shown that helical flanking sequences do not disrupt the assembly of a core cross-β-sheet structure, but such flanking sequences can influence higher order processes, such as inhibiting the bundling of the fibrils.