Chng, CP and Strange, RW (2014) 'Lipid-associated aggregate formation of superoxide dismutase-1 is initiated by membrane-targeting loops.' Proteins: Structure, Function and Bioinformatics, 82 (11). 3194 - 3209. ISSN 0887-3585

Text Proteins 2014 Chng.pdf Restricted to Repository staff only Download (1MB) | Request a copy

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.

Item Type:	Article
Subjects:	Q Science > QD Chemistry Q Science > QH Natural history > QH301 Biology
Divisions:	Faculty of Science and Health > Life Sciences, School of
Depositing User:	Richard Strange
Date Deposited:	08 Mar 2016 11:18
Last Modified:	09 Apr 2021 13:15
URI:	http://repository.essex.ac.uk/id/eprint/16220

Actions (login required)

View Item