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 H. Anjum, Ravindra Kodali, Trevor P. Creamer, James F. Conway, Angela M Gronenborn, Ronald Wetzel

Research output: Contribution to journalArticlepeer-review

357 Scopus citations


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
Pages (from-to)380-389
Number of pages10
JournalNature Structural and Molecular Biology
Issue number4
StatePublished - Apr 2009

Bibliographical note

Funding Information:
The authors acknowledge J. Ko and P. Patterson (California Institute of Technology) for the gift of the MW1 antibody, and T. Fullam (Allegheny College) for providing a set of aggregation kinetics data. We also acknowledge the following funding sources that contributed to the work described here: NIH R01 AG019322 (R.W.); Huntington’s Disease Society of America postdoctoral fellowship (V.M.C.); NSF MCB-0444049 (T.P.C.); Petroleum Research Fund/ American Chemical Society 43138-AC4 (T.P.C.); grant #4100026429 from the Commonwealth of Pennsylvania (A.M.G.).

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology


Dive into the research topics of 'Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanism'. Together they form a unique fingerprint.

Cite this