title: Negatively charged phospholipid membranes induce amyloid formation of medin via an alpha-helical intermediate.
abstract: Medin, a recently discovered 5.5 kDa peptide, is associated with amyloid deposits in the medial layer of human arteries and the prevalence is nearly 100% within individuals above 50 years. Presently, not much is known about its biochemical and biophysical properties or its pathway from soluble peptide to insoluble amyloid. Here we have characterized the behavior of medin in the presence of lipid membranes, using circular dichroism, isothermal titration calorimetry, differential scanning calorimetry, size exclusion chromatography, and atomic force microscopy (AFM). Medin was shown to exist as a monomer in solution with a predominantly random-coil structure. It binds lipid vesicles that have either a neutral or a negative surface potential. Upon association to membranes containing acidic lipids, it undergoes an electrostatically driven conformational change towards a mainly alpha-helical state. Prolonged incubation converts medin from an alpha-helical structure into an amyloid beta-sheet fibrillar state as confirmed by AFM. Based on these findings, we propose a mechanism of medin-amyloid formation where medin electrostatically associates in its monomeric form to biological interfaces displaying a negative potential. This process both increases the local peptide concentration and induces an aggregation-prone alpha-helical fold.
authors: Umeå Centre for Molecular Pathogenesis, Umeå University, 901 87, Umeå, Sweden.
authors: Anders
authors: A
authors: Olofsson
authors: Tomasz
authors: T
authors: Borowik
authors: Gerhard
authors: G
authors: Gröbner
authors: A Elisabeth
authors: AE
authors: Sauer-Eriksson
mesh_terms: D000954:Antigens, Surface / Q000737:chemistry* / Q000378:metabolism*; D002152:Calorimetry, Differential Scanning; D002850:Chromatography, Gel; D002942:Circular Dichroism; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry*; D018625:Microscopy, Atomic Force; D008894:Milk Proteins / Q000737:chemistry* / Q000378:metabolism*; D008961:Models, Structural; D010743:Phospholipids / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D000954:Antigens, Surface; D008051:Lipid Bilayers; C098942:MFGE8 protein, human; D008894:Milk Proteins; D010743:Phospholipids