Lipid‐associated aggregate formation of superoxide dismutase‐1 is initiated by membrane‐targeting loops |
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Authors: | Choon‐Peng Chng Richard W. Strange |
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Affiliation: | 1. Biophysical Modeling Group, Bioinformatics Institute, A*STAR (Agency for Science, Technology and Research), , Singapore, 138671 Republic of Singapore;2. Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, Life Sciences Building, Crown Street, The University of Liverpool, , Liverpool, L69 7ZB United Kingdom |
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Abstract: | Copper‐Zinc superoxide dismutase 1 (SOD1) is a homodimeric enzyme that protects cells from oxidative damage. Hereditary and sporadic amyotrophic lateral sclerosis may be linked to SOD1 when the enzyme is destabilized through mutation or environmental stress. The cytotoxicity of demetallated or apo‐SOD1 aggregates may be due to their ability to cause defects within cell membranes by co‐aggregating with phospholipids. SOD1 monomers may associate with the inner cell membrane to receive copper ions from membrane‐bound copper chaperones. But how apo‐SOD1 interacts with lipids is unclear. We have used atomistic molecular dynamics simulations to reveal that flexible electrostatic and zinc‐binding loops in apo‐SOD1 dimers play a critical role in the binding of 1‐octanol clusters and phospholipid bilayer, without any significant unfolding of the protein. The apo‐SOD1 monomer also associates with phospholipid bilayer via its zinc‐binding loop rather than its exposed hydrophobic dimerization interface. Our observed orientation of the monomer on the bilayer would facilitate its association with a membrane‐bound copper chaperone. The orientation also suggests how membrane‐bound monomers could act as seeds for membrane‐associated SOD1 aggregation. Proteins 2014; 82:3194–3209. © 2014 Wiley Periodicals, Inc. |
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Keywords: | amyotrophic lateral sclerosis motor neuron disease membrane‐targeting loops protein– lipid co‐aggregation 1‐octanol |
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