Nucleation Inhibition of Huntingtin Protein (htt) by Polyproline PPII Helices: A Potential Interaction with the N-Terminal α-Helical Region of Htt.

James R Arndt, Maxmore Chaibva, Maryssa Beasley, Ahmad Kiani Karanji, Samaneh Ghassabi Kondalaji, Mahdiar Khakinejad, Olivia Sarver, Justin Legleiter, Stephen J Valentine

Biochemistry 2020 Feb 04

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Huntington's disease is a genetic neurodegenerative disorder characterized by the formation of amyloid fibrils of the huntingtin protein (htt). The 17-residue N-terminal region of htt (Nt17) has been implicated in the 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 the formation of oligomers, 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 fibrillization has been examined by atomic force microscopy. From multiple, time-course experiments, morphological changes in oligomeric species are observed for the protein/peptide mixture and 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 been examined by ion mobility spectrometry and gas-phase hydrogen-deuterium exchange coupled with mass spectrometry. These data combined with molecular dynamics simulations suggest that the C-terminal region of Nt17 may be a primary point of contact. One interpretation of the results is that polyP may possibly regulate Nt17 by inducing a random coil region in the C-terminal portion of Nt17, thus decreasing the propensity to form the reactive amphipathic α-helix. A separate interpretation is that the residues important for helix-helix interactions are blocked by polyP association.

Citation

James R Arndt, Maxmore Chaibva, Maryssa Beasley, Ahmad Kiani Karanji, Samaneh Ghassabi Kondalaji, Mahdiar Khakinejad, Olivia Sarver, Justin Legleiter, Stephen J Valentine. Nucleation Inhibition of Huntingtin Protein (htt) by Polyproline PPII Helices: A Potential Interaction with the N-Terminal α-Helical Region of Htt. Biochemistry. 2020 Feb 04;59(4):436-449