Article abstract
Nature Structural & Molecular Biology 16, 380 - 389 (2009)
Published online: 8 March 2009 | doi:10.1038/nsmb.1570
Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism
Ashwani K Thakur1,2,4, Murali Jayaraman1,2,4, Rakesh Mishra1,2, Monika Thakur1,2, Veronique M Chellgren3, In-Ja L Byeon1, Dalaver H Anjum1, Ravindra Kodali1,2, Trevor P Creamer3, James F Conway1, Angela M Gronenborn1 & Ronald Wetzel1,2
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.
- Department of Structural Biology.
- Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536, USA.
- These authors contributed equally to this work.
Correspondence to: Ronald Wetzel1,2 e-mail: rwetzel@pitt.edu
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