The predicted structure of the headpiece of the Huntingtin protein and its implications on Huntingtin aggregation

J Mol Biol. 2009 May 22;388(5):919-27. doi: 10.1016/j.jmb.2009.01.032. Epub 2009 Jan 23.

Abstract

We have performed simulated tempering molecular dynamics simulations to study the thermodynamics of the headpiece of the Huntingtin (Htt) protein (N17(Htt)). With converged sampling, we found this peptide is highly helical, as previously proposed. Interestingly, this peptide is also found to adopt two different and seemingly stable states. The region from residue 4 (L) to residue 9 (K) has a strong helicity from our simulations, which is supported by experimental studies. However, contrary to what was initially proposed, we have found that simulations predict the most populated state as a two-helix bundle rather than a single straight helix, although a significant percentage of structures do still adopt a single linear helix. The fact that Htt aggregation is nucleation dependent infers the importance of a critical transition. It has been shown that N17(Htt) is involved in this rate-limiting step. In this study, we propose two possible mechanisms for this nucleating event stemming from the transition between two-helix bundle state and single-helix state for N17(Htt) and the experimentally observed interactions between the N17(Htt) and polyQ domains. More strikingly, an extensive hydrophobic surface area is found to be exposed to solvent in the dominant monomeric state of N17(Htt). We propose the most fundamental role played by N17(Htt) would be initializing the dimerization and pulling the polyQ chains into adequate spatial proximity for the nucleation event to proceed.

Publication types

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

MeSH terms

  • Computer Simulation*
  • Humans
  • Huntingtin Protein
  • Models, Molecular
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Probability
  • Protein Folding
  • Protein Multimerization*
  • Protein Structure, Secondary*
  • Thermodynamics

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins