Inhibition of huntingtin aggregation by its N-terminal 17-residue peptide and its analogs
2021
Belwal, Vinay Kumar | Vijayakumar, Aishwarya | Chaudhary, Nitin
The N-terminal 17-residue stretch of huntingtin (httᴺ¹⁷) folds into an amphipathic α-helix. The httᴺ¹⁷–harboring polyQ peptides form oligomers that are mediated via the assembly of the httᴺ¹⁷ α-helices. The oligomerization results in higher local concentration of the polyglutamine (polyQ) region, thereby facilitating amyloid formation. The httᴺ¹⁷ co-assembles with the httᴺ¹⁷-harbouring polyQ peptides, thereby reducing the local polyQ concentration, and consequently inhibiting aggregation. This study presents the aggregation inhibition of the exon I region of pathogenic huntingtin by httᴺ¹⁷ and its analogs. The C-terminal amidation of httᴺ¹⁷ is found to be essential for activity. The httᴺ¹⁷ peptides with free amino terminus and the acetylated amino terminus possess comparable activity. The httᴺ¹⁷ analog, wherein the Leu7 and Ala10 are substituted with 2-aminoisobutyric acid residues, exhibits significantly higher activity than the native httᴺ¹⁷.
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