A structural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins

J Mol Biol. 2003 Jun 13;329(4):763-78. doi: 10.1016/s0022-2836(03)00520-5.

Abstract

We have used NMR spectroscopy and limited proteolysis to characterize the structural properties of the Parkinson's disease-related protein alpha-synuclein in lipid and detergent micelle environments. We show that the lipid or micelle surface-bound portion of the molecule adopts a continuously helical structure with a single break. Modeling alphaS as an ideal alpha-helix reveals a hydrophobic surface that winds around the helix axis in a right-handed fashion. This feature is typical of 11-mer repeat containing sequences that adopt right-handed coiled coil conformations. In order to bind a flat or convex lipid surface, however, an unbroken helical alphaS structure would need to adopt an unusual, slightly unwound, alpha11/3 helix conformation (three complete turns per 11 residues). The break we observe in the alphaS helix may allow the protein to avoid this unusual conformation by adopting two shorter stretches of typical alpha-helical structure. However, a quantitative analysis suggests the possibility that the alpha11/3 conformation may in fact exist in lipid-bound alphaS. We discuss how structural features of helical 11-mer repeats could play a role in the reversible lipid binding function of alpha-synuclein and generalize this argument to include the 11-mer repeat-containing apolipoproteins, which also require the ability to release readily from lipid surfaces. A search of protein sequence databases confirms that synuclein-like 11-mer repeats are present in other proteins that bind lipids reversibly and predicts such a role for a number of hypothetical proteins of unknown function.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Carbon / metabolism
  • Circular Dichroism
  • Humans
  • Lipid Metabolism*
  • Liposomes / chemistry
  • Liposomes / metabolism
  • Magnetic Resonance Spectroscopy
  • Micelles
  • Models, Molecular
  • Molecular Sequence Data
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / metabolism*
  • Nitrogen / metabolism
  • Parkinson Disease
  • Protein Binding
  • Protein Conformation
  • Protein Folding
  • Protons
  • Sodium Dodecyl Sulfate / metabolism
  • Synucleins
  • alpha-Synuclein

Substances

  • Liposomes
  • Micelles
  • Nerve Tissue Proteins
  • Protons
  • SNCA protein, human
  • Synucleins
  • alpha-Synuclein
  • Sodium Dodecyl Sulfate
  • Carbon
  • Nitrogen