Interaction of Huntingtin Exon-1 Peptides with Lipid-Based Micellar Nanoparticles Probed by Solution NMR and Q-Band Pulsed EPR

J Am Chem Soc. 2018 May 23;140(20):6199-6202. doi: 10.1021/jacs.8b02619. Epub 2018 May 14.

Abstract

Lipid-based micellar nanoparticles promote aggregation of huntingtin exon-1 peptides. Here we characterize the interaction of two such peptides, httNTQ 7 and httNTQ 10 comprising the N-terminal amphiphilic domain of huntingtin followed by 7 and 10 glutamine repeats, respectively, with 8 nm lipid micelles using NMR chemical exchange saturation transfer (CEST), circular dichroism and pulsed Q-band EPR. Exchange between free and micelle-bound httNTQ n peptides occurs on the millisecond time scale with a KD ∼ 0.5-1 mM. Upon binding micelles, residues 1-15 adopt a helical conformation. Oxidation of Met7 to a sulfoxide reduces the binding affinity for micelles ∼3-4-fold and increases the length of the helix by a further two residues. A structure of the bound monomer unit is calculated from the backbone chemical shifts of the micelle-bound state obtained from CEST. Pulsed Q-band EPR shows that a monomer-dimer equilibrium exists on the surface of the micelles and that the two helices of the dimer adopt a parallel orientation, thereby bringing two disordered polyQ tails into close proximity which may promote aggregation upon dissociation from the micelle surface.

Publication types

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

MeSH terms

  • Electron Spin Resonance Spectroscopy
  • Humans
  • Huntingtin Protein / chemistry*
  • Lipids / chemistry*
  • Micelles*
  • Models, Molecular
  • Nanoparticles / chemistry*
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptides / chemistry
  • Protein Aggregates
  • Protein Conformation, alpha-Helical
  • Protein Domains
  • Protein Multimerization

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Lipids
  • Micelles
  • Peptides
  • Protein Aggregates
  • polyglutamine