Membrane-mediated peptide conformation change from alpha-monomers to beta-aggregates.
Jarrett and Lansbury's nucleation-dependent polymerization model describes the generic process of beta-amyloid formation for a large number of diverse proteins and peptides. Here, we discuss a case of membrane-mediated nucleation that leads to beta-aggregation. We studied the membrane-mediated conformation changes of the peptide penetratin, and the results of our study led us to a free-energy description for a membrane-mediated version of the Jarrett-Lansbury model. Like the prototype beta-amyloid peptide Alzheimer's Abeta 1-40, penetratin is a random-coil monomer in solution but changes to alpha-helical or beta-like conformations in the presence of anionic lipid membranes. We measured the correlations between the membrane-bound conformation of penetratin and its effect on the bilayer thickness in four different lipids with various degrees of chain unsaturation. We found a new lipid chain effect on peptide conformation. Our results showed that the interface of a lipid bilayer provided energetically favorable binding sites for penetratin in the alpha-helical form. However, increasing the bound molecules/lipid ratio elevated the energy level of the bound states toward a higher level that favored creation of small beta-aggregates. The binding to the beta-aggregate became more energetically favorable as the aggregate grew larger. The peptide aggregates were visible on the surface of giant unilamellar vesicles. Thus, membrane binding facilitates nucleation-dependent beta-aggregation, which could be the prototype for the general membrane-mediated pathway to beta-amyloid formation.
Lee
Chang-Chun
CC
Department of Physics and Astronomy, Rice University, Houston, Texas.
Sun
Yen
Y
Huang
Huey W
HW
D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity; D006801:Humans; D008563:Membrane Lipids / Q000633:toxicity; D008566:Membranes / Q000737:chemistry*; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry / Q000633:toxicity*; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding / Q000187:drug effects*; D017433:Protein Structure, Secondary / Q000502:physiology*
D016229:Amyloid beta-Peptides; D008563:Membrane Lipids; D010455:Peptides