Effects of Lipid Composition and Phase on the Membrane Interaction of the Prion Peptide 106–126 Amide

AbstractLipid rafts are specialized liquid-ordered (Lo) phases of the cell membrane that are enriched in sphingolipids and cholesterol (Chl), and surrounded by a liquid-disordered (Ld) phase enriched in glycerophospholipids. Lipid rafts are involved in the generation of pathological forms of proteins that are associated with neurodegenerative diseases. To investigate the effects of lipid composition and phase on the generation of pathological forms of proteins, we constructed an Ld-gel phase-separated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/sphingomyelin (from bovine brain (BSM))-supported lipid bilayer (SLB) and an Ld-Lo phase-separated POPC/BSM/Chl SLB. We used in situ time-lapse atomic force microscopy to study the interactions between these SLBs and the prion peptide K106TNMKHMAGAAAAGAVVGGLG126 (PrP106–126) amide, numbered according to the human prion-peptide sequence. Our results show that: 1), with the presence of BSM in the Ld phase, the PrP106–126 amide induces fully penetrated porations in the Ld phase of POPC/BSM SLB and POPC/BSM/Chl SLB; 2), with the presence of both BSM and Chl in the Ld phase, the PrP106–126 amide induces the disintegration of the Ld phase of POPC/BSM/Chl SLB; and 3), with the presence of both BSM and Chl in the Lo phase, PrP106–126 amide induces membrane thinning in the Lo phase of POPC/BSM/Chl SLB. These results provide comprehensive insight into the process by which the PrP106–126 amide interacts with lipid membranes