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Article Abstract
The N-terminal 17-residue stretch of huntingtin (htt) folds into an amphipathic α-helix. The htt-harboring polyQ peptides form oligomers that are mediated via the assembly of the htt α-helices. The oligomerization results in higher local concentration of the polyglutamine (polyQ) region, thereby facilitating amyloid formation. The htt co-assembles with the htt-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 htt and its analogs. The C-terminal amidation of htt is found to be essential for activity. The htt peptides with free amino terminus and the acetylated amino terminus possess comparable activity. The htt analog, wherein the Leu7 and Ala10 are substituted with 2-aminoisobutyric acid residues, exhibits significantly higher activity than the native htt.
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| http://dx.doi.org/10.1016/j.abb.2021.109033 | DOI Listing |
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Inhibition of huntingtin aggregation by its N-terminal 17-residue peptide and its analogs.
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Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781 039, India. Electronic address:
The N-terminal 17-residue stretch of huntingtin (htt) folds into an amphipathic α-helix. The htt-harboring polyQ peptides form oligomers that are mediated via the assembly of the htt α-helices. The oligomerization results in higher local concentration of the polyglutamine (polyQ) region, thereby facilitating amyloid formation.
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Max-Planck-Institut für Kohlenforschung , 45470 Mülheim an der Ruhr, Germany.
Huntington's disease is a neurodegenerative disorder associated with the expansion of the polyglutamine tract in the exon-1 domain of the huntingtin protein (htt). Above a threshold of 37 glutamine residues, htt starts to aggregate in a nucleation-dependent manner. A 17-residue N-terminal fragment of htt (N17) has been suggested to play a crucial role in modulating the aggregation propensity and toxicity of htt.
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