Physiologically-relevant levels of sphingomyelin, but not GM1, induces a beta-sheet-rich structure in the amyloid-beta(1-42) monomer

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Owen , M C , Kulig , W , Poojari , C , Rog , T & Strodel , B 2018 , ' Physiologically-relevant levels of sphingomyelin, but not GM1, induces a beta-sheet-rich structure in the amyloid-beta(1-42) monomer ' , Biochimica et Biophysica Acta. Biomembranes , vol. 1860 , no. 9 , pp. 1709-1720 . https://doi.org/10.1016/j.bbamem.2018.03.026

Title: Physiologically-relevant levels of sphingomyelin, but not GM1, induces a beta-sheet-rich structure in the amyloid-beta(1-42) monomer
Author: Owen, Michael C.; Kulig, Waldemar; Poojari, Chetan; Rog, Tomasz; Strodel, Birgit
Contributor: University of Helsinki, Department of Physics
University of Helsinki, Department of Physics
University of Helsinki, Department of Physics
Date: 2018-09
Language: eng
Number of pages: 12
Belongs to series: Biochimica et Biophysica Acta. Biomembranes
ISSN: 0005-2736
URI: http://hdl.handle.net/10138/300673
Abstract: To resolve the contribution of ceramide-containing lipids to the aggregation of the amyloid-β protein into β-sheet rich toxic oligomers, we employed molecular dynamics simulations to study the effect of cholesterol-containing bilayers comprised of POPC (70% POPC, and 30% cholesterol) and physiologically relevant concentrations of sphingomyelin (SM) (30% SM, 40% POPC, and 30% cholesterol), and the GM1 ganglioside (5% GM1, 70% POPC, and 25% cholesterol). The increased bilayer rigidity provided by SM (and to a lesser degree, GM1) reduced the interactions between the SM-enriched bilayer and the N-terminus of Aβ42 (and also residues Ser26, Asn27, and Lys28), which facilitated the formation of a β-sheet in the normally disordered N-terminal region. Aβ42 remained anchored to the SM-enriched bilayer through hydrogen bonds with the side chain of Arg5. With β-sheets in the at the N and C termini, the structure of Aβ42 in the sphingomyelin-enriched bilayer most resembles β-sheet-rich structures found in higher-ordered Aβ fibrils. Conversely, when bound to a bilayer comprised of 5% GM1, the conformation remained similar to that observed in the absence of GM1, with Aβ42 only making contact with one or two GM1 molecules. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.
Subject: Peptide-membrane interactions
Sphingomyelin
Lipid rafts
Amyloid-β peptide
Molecular dynamics
Membrane simulations
GM1
Gangliosides
Peptide-ganglioside interactions
MEMBRANE DISRUPTION
MOLECULAR-DYNAMICS
FIBRIL STRUCTURE
ALZHEIMERS-DISEASE
PEPTIDE
AMYLOID-BETA
Amyloid-beta peptide
A-BETA
FORCE-FIELD
PHOSPHOLIPID-BILAYERS
LIPID-BILAYER
1182 Biochemistry, cell and molecular biology
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