DOI: 10.1021/la901750v 12501 Langmuir 2009, 25(21), 12501–12506 Published on Web 07/09/2009 pubs.acs.org/Langmuir © 2009 American Chemical Society Phospholipid-Induced Fibrillation of a Prion Amyloidogenic Determinant at the Air/Water Interface Jerzy Dorosz, Roman Volinsky, Ehud Bazar, Sofiya Kolusheva, and Raz Jelinek* Department of Chemistry and Ilse Katz Institute of Nanotechnology, Ben Gurion University, Beer Sheva 84105, Israel Received May 18, 2009. Revised Manuscript Received June 16, 2009 The peptide fragment 106-126 of prion protein [PrP(106-126)] is a prominent amyloidogenic determinant. We present analysis of PrP(106-126) fibrillation at the air/water interface and, in particular, the relationship between the fibrillation process and interactions of the peptide with phospholipid monolayers. We find that lipid monolayers deposited at the air/water interface induce rapid formation of remarkably highly ordered fibrils by PrP(106-126), and that the extent of fibrillation and fiber organization were dependent upon the presence of negatively charged and unsaturated phospholipids in the monolayers. We also observe that fibrillation was enhanced when PrP(106-126) was injected underneath preassembled phospholipid monolayers, compared to deposition and subsequent compression of mixed monolayers of the peptide and phospholipids. In a broader context, this study demonstrates that Langmuir systems constitute a useful platform for studying lipid interactions of amyloidogenic peptides and lipid-induced fibrillation phenomena. Introduction Prion diseases encompass several devastating neurological conditions which are believed to be caused by infectious misfolded protein species 1 . The primary pathological feature of prion diseases is the conversion of the normal cellular prion protein (PrPc) to the aberrant isoform (PrPsc) in a post-translational process involving significant secondary structure changes 2 . The abnormal, protease-resistant isoform is rich in beta-sheet and aggregates into amyloid fibrils which are often found in brains of affected persons 2 . A fragment of human prion protein spanning residues 106-126 [amino-acid sequence KTNMKHMAGA- AAAGAVVGGLG, referred to as PrP(106-126)] has been a widely used model peptide for studying the pathogenic character- istics of full-length PrP because it retains important features of the full-length protein. In particular, PrP(106-126) is highly amylo- idogenic 3 and neurotoxic 4-6 . While the occurrence of amyloid fibrils in prion diseases is common, the exact functions of these structures as toxic factors or their direct pathological consequences are still unclear 7 . In recent years it has become increasingly apparent that mem- brane interactions of prion proteins and other amyloidogenic proteins play important roles in fibrillation and toxicity 8-13 . Indeed, toxic effects of amyloidogenic peptides are increas- ingly ascribed to pore formation and other bilayer disrup- tion events 14 . There are however indications that fibrillar aggregates or the fibrillation process itself may also be cyto- toxic 15-17 . Previous studies have revealed the lipid molecules intimately affect the misfolding pathways of amyloidogenic proteins 18,19 . Binding of amyloidogenic peptides to specific lipid molecules and membrane domains has been widely observed 9,20-22 , and several theories propose that membrane-induced fibrillation is a critical initial step in amyloidogenesis 23-25 . 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