Monomeric Huntingtin Exon 1 Has Similar Overall Structural Features for Wild-Type and Pathological Polyglutamine Lengths

J Am Chem Soc. 2017 Oct 18;139(41):14456-14469. doi: 10.1021/jacs.7b06659. Epub 2017 Oct 9.


Huntington's disease is caused by expansion of a polyglutamine (polyQ) domain within exon 1 of the huntingtin gene (Httex1). The prevailing hypothesis is that the monomeric Httex1 protein undergoes sharp conformational changes as the polyQ length exceeds a threshold of 36-37 residues. Here, we test this hypothesis by combining novel semi-synthesis strategies with state-of-the-art single-molecule Förster resonance energy transfer measurements on biologically relevant, monomeric Httex1 proteins of five different polyQ lengths. Our results, integrated with atomistic simulations, negate the hypothesis of a sharp, polyQ length-dependent change in the structure of monomeric Httex1. Instead, they support a continuous global compaction with increasing polyQ length that derives from increased prominence of the globular polyQ domain. Importantly, we show that monomeric Httex1 adopts tadpole-like architectures for polyQ lengths below and above the pathological threshold. Our results suggest that higher order homotypic and/or heterotypic interactions within distinct sub-populations of neurons, which are inevitable at finite cellular concentrations, are likely to be the main source of sharp polyQ length dependencies of HD.

Publication types

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

MeSH terms

  • Exons / genetics*
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Huntingtin Protein / genetics*
  • Huntingtin Protein / metabolism*
  • Huntington Disease / genetics
  • Peptides / genetics*
  • Peptides / metabolism*
  • Proline / metabolism
  • Reproducibility of Results


  • Huntingtin Protein
  • Peptides
  • polyglutamine
  • Proline