Membrane Interactions of the Amphipathic Amino Terminus of Huntingtin

Biochemistry. 2013 Feb 5;52(5):847-58. doi: 10.1021/bi301325q. Epub 2013 Jan 28.

Abstract

The amino-terminal domain of huntingtin (Htt17), located immediately upstream of the decisive polyglutamine tract, strongly influences important properties of this large protein and thereby the development of Huntington's disease. Htt17 markedly increases polyglutamine aggregation rates and the level of huntingtin's interactions with biological membranes. Htt17 adopts a largely helical conformation in the presence of membranes, and this structural transition was used to quantitatively analyze membrane association as a function of lipid composition. The apparent membrane partitioning constants increased in the presence of anionic lipids but decreased with increasing amounts of cholesterol. When membrane permeabilization was tested, a pronounced dye release was observed from 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) vesicles and 75:25 (molar ratio) POPC/1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine vesicles but not across bilayers that better mimic cellular membranes. Solid-state nuclear magnetic resonance structural investigations indicated that the Htt17 α-helix adopts an alignment parallel to the membrane surface, and that the tilt angle (∼75°) was nearly constant in all of the membranes that were investigated. Furthermore, the addition of Htt17 resulted in a decrease in the lipid order parameter in all of the membranes that were investigated. The lipid interactions of Htt17 have pivotal implications for membrane anchoring and functional properties of huntingtin and concomitantly the development of the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Membrane / chemistry*
  • Cell Membrane / metabolism*
  • Humans
  • Huntingtin Protein
  • Lipid Bilayers / chemistry
  • Lipid Bilayers / metabolism
  • Liposomes / chemistry
  • Liposomes / metabolism
  • Models, Molecular
  • Molecular Sequence Data
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / metabolism*
  • Permeability
  • Phosphatidylcholines / chemistry
  • Phosphatidylcholines / metabolism
  • Phosphatidylserines / chemistry
  • Phosphatidylserines / metabolism
  • Protein Structure, Secondary
  • Protein Structure, Tertiary

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Lipid Bilayers
  • Liposomes
  • Nerve Tissue Proteins
  • Phosphatidylcholines
  • Phosphatidylserines
  • 1-palmitoyl-2-oleoylglycero-3-phosphoserine
  • 1-palmitoyl-2-oleoylphosphatidylcholine