Nucleation inhibition of Huntingtin protein (htt) by polyproline PPII helices: a potential interaction with the N-terminal α-helical region of htt

Huntington’s disease (HD) is a genetic neurodegenerative disorder characterized by the formation of amyloid fibrils of the huntingtin protein (htt). The seventeen-residue N-terminal region of htt (Nt17) has been implicated in formation of early-phase oligomeric species, which may be neurotoxic. Because tertiary interactions with a downstream (C-terminal) polyproline (polyP) region of htt may disrupt oligomer formation which are precursors to fibrillar species, the effect of co-incubation of a region of htt with a 10-residue polyP peptide on oligomerization and fibrilization has been examined by atomic force microscopy (AFM). From multiple, time-course experiments, morphological changes in oligomeric species are observed for the protein/peptide mixture compared with the protein alone. Additionally, an overall decrease in fibril formation is observed for the heterogeneous mixture. To consider potential sites of interaction between the Nt17 region and polyP, mixtures containing Nt17 and polyP peptides have b...