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Abstract
Simple polyglutamine (polyQ) peptides aggregate in vitro via a nucleated growth pathway directly yielding amyloid-like aggregates. We show here that the 17-amino-acid flanking sequence (HTTNT) N-terminal to the polyQ in the toxic huntingtin exon 1 fragment imparts onto this peptide a complex alternative aggregation mechanism. In isolation, the HTTNT peptide is a compact coil that resists aggregation. When polyQ is fused to this sequence, it induces in HTTNT, in a repeat-length dependent fashion, a more extended conformation that greatly enhances its aggregation into globular oligomers with HTTNT cores and exposed polyQ. In a second step, a new, amyloid-like aggregate is formed with a core composed of both HTTNT and polyQ. The results indicate unprecedented complexity in how primary sequence controls aggregation within a substantially disordered peptide and have implications for the molecular mechanism of Huntington's disease.
Document Type
Article
Publication Date
4-2009
Digital Object Identifier (DOI)
http://dx.doi.org/10.1038/nsmb.1570
Repository Citation
Thakur, Ashwani K.; Jayaraman, Murali; Mishra, Rakesh; Thakur, Monika; Chellgren, Veronique M.; Byeon, In-Ja L; Anjum, Dalaver H.; Kodali, Ravindra; Creamer, Trevor P.; Conway, James F.; Gronenborn, Angela M.; and Wetzel, Ronald, "Polyglutamine Disruption of the Huntingtin Exon 1 N Terminus Triggers a Complex Aggregation Mechanism" (2009). Molecular and Cellular Biochemistry Faculty Publications. 46.
https://uknowledge.uky.edu/biochem_facpub/46
Notes/Citation Information
Published in Nature Structural & Molecular Biology, v. 16, no. 4, p. 380-389.
The document available for download is the authors' post-peer-review final draft of the article.