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Free cholesterol induces higher ?-sheet content in A? peptide oligomers by aromatic interaction with Phe19.

ABSTRACT: Accumulating experimental evidence support an enhancing effect of free cholesterol on amyloid-beta (A?) aggregation. To probe the mechanisms of cholesterol-mediated A? aggregation, we applied all-atom molecular dynamic simulations on A?42 peptides in presence of free cholesterol. Several control systems were also designed to examine the specificity of cholesterol-residue interactions, including mutation on aromatic residue, substitution of cholesterol with sphingomyelin (SM) and DPPC bilayer, and a mixing SM and cholesterol. Each system was performed 4 independent simulations, with a total time of 560 ns. It was found that cholesterol increased ?-sheet formation by 4 folds, but the Phe19?Ser mutation on A?42 peptide totally eliminated cholesterol's effect. A stable contact was recognized between the steroid group of cholesterol and the Benzyl group of Phe19. Interestingly, our simulation revealed a regular 1 ns time interval between the establishment of cholesterol-phenylalanine contact and consequent ?-sheet formation, suggesting an important role of steroid-benzyl interaction in cholesterol-mediated aggregation. The presence of SM slightly increased ?-sheet formation, but the mixture of cholesterol and SM had a strong induction effect. Also, the measurement of Phe19-lipid distance indicates that aromatic side chains of peptides prone to bind to cholesterol on the surface of the mixed micelle. In the DPPC system, polar chains were attracted to the surface of membrane, yielding moderate increase of ?-sheet formation. These results shed light on the mechanism of cholesterol-mediated fibrillogenesis, and help to differentiate the effects of cholesterol and other lipids on ?-sheet formation process.

SUBMITTER: Zhou X

PROVIDER: S-EPMC3458103 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Free cholesterol induces higher β-sheet content in Aβ peptide oligomers by aromatic interaction with Phe19.

Zhou Xiaolin X Xu Jie J

PloS one 20120925 9

Accumulating experimental evidence support an enhancing effect of free cholesterol on amyloid-beta (Aβ) aggregation. To probe the mechanisms of cholesterol-mediated Aβ aggregation, we applied all-atom molecular dynamic simulations on Aβ42 peptides in presence of free cholesterol. Several control systems were also designed to examine the specificity of cholesterol-residue interactions, including mutation on aromatic residue, substitution of cholesterol with sphingomyelin (SM) and DPPC bilayer, an ...[more]

PMID: 23049991

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Project description:The formation of ?-sheet rich prion oligomers and fibrils from native prion protein (PrP) is thought to be a key step in the development of prion diseases. Many methods are available to convert recombinant prion protein into ?-sheet rich fibrils using various chemical denaturants (urea, SDS, GdnHCl), high temperature, phospholipids, or mildly acidic conditions (pH 4). Many of these methods also require shaking or another form of agitation to complete the conversion process. We have identified that shaking alone causes the conversion of recombinant PrP to ?-sheet rich oligomers and fibrils at near physiological pH (pH 5.5 to pH 6.2) and temperature. This conversion does not require any denaturant, detergent, or any other chemical cofactor. Interestingly, this conversion does not occur when the water-air interface is eliminated in the shaken sample. We have analyzed shaking-induced conversion using circular dichroism, resolution enhanced native acidic gel electrophoresis (RENAGE), electron microscopy, Fourier transform infrared spectroscopy, thioflavin T fluorescence and proteinase K resistance. Our results show that shaking causes the formation of ?-sheet rich oligomers with a population distribution ranging from octamers to dodecamers and that further shaking causes a transition to ?-sheet fibrils. In addition, we show that shaking-induced conversion occurs for a wide range of full-length and truncated constructs of mouse, hamster and cervid prion proteins. We propose that this method of conversion provides a robust, reproducible and easily accessible model for scrapie-like amyloid formation, allowing the generation of milligram quantities of physiologically stable ?-sheet rich oligomers and fibrils. These results may also have interesting implications regarding our understanding of prion conversion and propagation both within the brain and via techniques such as protein misfolding cyclic amplification (PMCA) and quaking induced conversion (QuIC).

Dataset Information

Free cholesterol induces higher ?-sheet content in A? peptide oligomers by aromatic interaction with Phe19.

Publications

Free cholesterol induces higher β-sheet content in Aβ peptide oligomers by aromatic interaction with Phe19.

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