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

Nat Struct Mol Biol. 2009 Apr;16(4):380-9. doi: 10.1038/nsmb.1570. Epub 2009 Mar 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Circular Dichroism
  • Humans
  • Huntingtin Protein
  • Kinetics
  • Macromolecular Substances / metabolism
  • Magnetic Resonance Spectroscopy
  • Microscopy, Electron, Transmission
  • Models, Biological
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / metabolism*
  • Nerve Tissue Proteins / ultrastructure
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Nuclear Proteins / ultrastructure
  • Peptides / chemical synthesis
  • Peptides / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Multimerization*

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Macromolecular Substances
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • polyglutamine