Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism

Ashwani K. Thakur, Murali Jayaraman, Rakesh Mishra, Monika Thakur, Veronique M. Chellgren, In Ja L Byeon, Dalaver Anjum, Ravindra Kodali, Trevor P. Creamer, James F. Conway, Angela M Gronenborn, Ronald Wetzel*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    321 Scopus citations

    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 (HTT NT) N-terminal to the polyQ in the toxic huntingtin exon 1 fragment imparts onto this peptide a complex alternative aggregation mechanism. In isolation, the HTT NT peptide is a compact coil that resists aggregation. When polyQ is fused to this sequence, it induces in HTT NT, in a repeat-length dependent fashion, a more extended conformation that greatly enhances its aggregation into globular oligomers with HTT NT cores and exposed polyQ. In a second step, a new, amyloid-like aggregate is formed with a core composed of both HTT NT 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.

    Original languageEnglish (US)
    Pages (from-to)380-389
    Number of pages10
    JournalNature Structural and Molecular Biology
    Volume16
    Issue number4
    DOIs
    StatePublished - Apr 1 2009

    ASJC Scopus subject areas

    • Structural Biology
    • Molecular Biology

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