Membrane interactions of a self-assembling model peptide that mimics the self-association, structure and toxicity of Abeta(1-40).
Beta-amyloid peptide (Abeta) is a primary protein component of senile plaques in Alzheimer's disease (AD) and plays an important, but not fully understood role in neurotoxicity. Model peptides with the demonstrated ability to mimic the structural and toxicity behavior of Abeta could provide a means to evaluate the contributions to toxicity that are common to self-associating peptides from many disease states. In this work, we have studied the peptide-membrane interactions of a model beta-sheet peptide, P(11-2) (CH(3)CO-Gln-Gln-Arg-Phe-Gln-Trp-Gln-Phe-Glu-Gln-Gln-NH(2)), by fluorescence, infrared spectroscopy, and hydrogen-deuterium exchange. Like Abeta(1-40), the peptide is toxic, and conditions which produce intermediate oligomers show higher toxicity against cells than either monomeric forms or higher aggregates of the peptide. Further, P(11-2) also binds to both zwitterionic (POPC) and negatively charged (POPC:POPG) liposomes, acquires a partial beta-sheet conformation in presence of lipid, and is protected against deuterium exchange in the presence of lipids. The results show that a simple rationally designed model beta-sheet peptide recapitulates many important features of Abeta peptide structure and function, reinforcing the idea that toxicity arises, at least in part, from a common mode of action on membranes that is independent of specific aspects of the amino acid sequence. Further studies of such well-behaved model peptide systems will facilitate the investigation of the general principles that govern the molecular interactions of aggregation-prone disease-associated peptides with cell and/or membrane surfaces.
Salay
Luiz C
LC
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
Qi
Wei
W
Keshet
Ben
B
Tamm
Lukas K
LK
Fernandez
Erik J
EJ
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D041961:Deuterium Exchange Measurement; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D013058:Mass Spectrometry; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity*; D010455:Peptides / Q000737:chemistry* / Q000633:toxicity*; D010715:Phosphatidylglycerols / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared
D016229:Amyloid beta-Peptides; D008081:Liposomes; D010446:Peptide Fragments; D010455:Peptides; D010715:Phosphatidylglycerols; C544323:acetyl-glutaminyl-glutaminyl-arginyl-phenylalanyl-glutaminyl-tryptophyl-glutaminyl-phenylalanyl-glutamyl-glutaminyl-glutaminamide; C078592:amyloid beta-protein (1-40); C060037:1-palmitoyl-2-oleoylglycero-3-phosphoglycerol