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Negatively charged phospholipid membranes induce amyloid formation of medin via an alpha-helical intermediate

Anders Olofsson1, Tomasz Borowik, Gerhard Gröbner

  • 1Umeå Centre for Molecular Pathogenesis, Umeå University, 901 87, Umeå, Sweden.

Journal of Molecular Biology
|October 2, 2007
PubMed

Insights

Medin peptide, found in arteries of individuals over 50, transforms from a random coil to an alpha-helical structure upon binding to negatively charged lipid membranes, eventually forming amyloid fibrils.

Area of Science:

  • Biochemistry
  • Biophysics
  • Molecular Biology

Background:

  • Medin is a 5.5 kDa peptide found in human artery amyloid deposits, prevalent in individuals over 50.
  • Its biochemical properties and amyloid formation pathway remain largely uncharacterized.

Purpose of the Study:

  • To characterize the behavior of medin in the presence of lipid membranes.
  • To elucidate the pathway of medin from soluble peptide to insoluble amyloid.

Main Methods:

  • Circular dichroism (CD)
  • Isothermal titration calorimetry (ITC)
  • Differential scanning calorimetry (DSC)
  • Size exclusion chromatography (SEC)
  • Atomic force microscopy (AFM)

Main Results:

  • Medin exists as a monomer with a random-coil structure in solution.
  • Medin binds to lipid vesicles with neutral or negative surface potentials.
  • Association with acidic lipids induces an electrostatically driven conformational change to an alpha-helical state.
  • Prolonged incubation leads to the formation of beta-sheet amyloid fibrils.

Conclusions:

  • Medin forms amyloid fibrils via an electrostatically driven mechanism.
  • Monomeric medin associates with negatively charged biological interfaces.
  • This interaction increases local peptide concentration and induces an aggregation-prone alpha-helical fold, initiating amyloid formation.

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