Membrane Remodeling by α-synuclein and Effects on Amyloid Formation

J Am Chem Soc. 2013 Oct 30;135(43):15970-3. doi: 10.1021/ja405993r. Epub 2013 Oct 17.

Abstract

α-Synuclein (α-Syn), an intrinsically disordered protein, is associated with Parkinson's disease. Though molecular pathogenic mechanisms are ill-defined, mounting evidence connects its amyloid forming and membrane binding propensities to disease etiology. Contrary to recent data suggesting that membrane remodeling by α-syn involves anionic phospholipids and helical structure, we discovered that the protein deforms vesicles with no net surface charge (phosphatidylcholine, PC) into tubules (average diameter ∼20 nm). No discernible secondary structural changes were detected by circular dichroism spectroscopy upon the addition of vesicles. Notably, membrane remodeling inhibits α-syn amyloid formation affecting both lag and growth phases. Using five single tryptophan variants and time-resolved fluorescence anisotropy measurements, we determined that α-syn influences bilayer structure with surprisingly weak interaction and no site specificity (partition constant, Kp ∼ 300 M(-1)). Vesicle deformation by α-syn under a variety of different lipid/protein conditions is characterized via transmission electron microscopy. As cellular membranes are enriched in PC lipids, these results support possible biological consequences for α-syn induced membrane remodeling related to both function and pathogenesis.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / chemistry
  • Amyloid / chemistry*
  • Cholesterol / chemistry
  • Circular Dichroism
  • Glycerophospholipids / chemistry
  • Indicators and Reagents
  • Lipid Bilayers
  • Lipids / chemistry
  • Membranes, Artificial*
  • Microscopy, Electron, Transmission
  • Microtubules
  • Neutrons
  • Phosphatidylcholines
  • Spectrophotometry, Ultraviolet
  • Tryptophan / chemistry
  • alpha-Synuclein / chemistry*

Substances

  • 1-palmitoyl-2-oleoyl-phosphatidyl-3-adenosine
  • Amyloid
  • Glycerophospholipids
  • Indicators and Reagents
  • Lipid Bilayers
  • Lipids
  • Membranes, Artificial
  • Phosphatidylcholines
  • alpha-Synuclein
  • Tryptophan
  • Cholesterol
  • Adenosine
  • 1-palmitoyl-2-oleoylphosphatidylcholine