Competing discrete interfacial effects are critical for amyloidogenesis.
Amyloid accumulation is associated with pathological conditions, including type II diabetes and Alzheimer's disease. Lipids influence amyloidogenesis and are themselves targets for amyloid-mediated cell membrane disruption. Amyloid precursors are surface-active, accumulating at hydrophobic-hydrophilic interfaces (e.g., air-water), where their biophysical and kinetic behaviors differ from those in the bulk solution with significant and underappreciated consequences. Biophysical modeling predicted the probability and rate of beta-sheet amyloid dimer formation to be higher and faster at the air-water interface (AWI) than in the bulk (by 14 and approximately 1500 times, respectively). Time-course staining experiments with a typical amyloid dye verified our predictions by demonstrating that without AWI, islet amyloid polypeptide (IAPP) fibrilization was abolished or slowed, depending on the conditions. Our controls included undisturbed IAPP reactions, and we ascertained that the AWI removal process (technical or material) did not itself affect the reaction. Furthermore, we showed that the role of membranes in amyloidogenesis has been previously underestimated; in an in vivo-like situation (with no AWI), anionic liposomes (containing dioleoylphosphatidylglycerol) enhanced IAPP fibrilogenesis far more than described previously in conventional assay conditions (in the presence of an AWI). These findings have implications for the protein misfolding field and in assay design to target toxic protein aggregation.
Jean
Létitia
L
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, UK.
Lee
Chiu Fan
CF
Lee
Chongsoo
C
Shaw
Michael
M
Vaux
David J
DJ
D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry*; D019281:Dimerization; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D058228:Islet Amyloid Polypeptide; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D008081:Liposomes; D008823:Micelles; D008954:Models, Biological; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry; D013500:Surface Tension; D013501:Surface-Active Agents / Q000737:chemistry / Q000378:metabolism
D000682:Amyloid; D058228:Islet Amyloid Polypeptide; D008055:Lipids; D008081:Liposomes; D008823:Micelles; D011994:Recombinant Proteins; D013501:Surface-Active Agents