title: Effect of Oxidative Damage on the Stability and Dimerization of Superoxide Dismutase 1.
abstract: During their life cycle, proteins are subject to different modifications involving reactive oxygen species. Such oxidative damage to proteins may lead to the formation of insoluble aggregates and cytotoxicity and is associated with age-related disorders including neurodegenerative diseases, cancer, and diabetes. Superoxide dismutase 1 (SOD1), a key antioxidant enzyme in human cells, is particularly susceptible to such modifications. Moreover, this homodimeric metalloenzyme has been directly linked to both familial and sporadic amyotrophic lateral sclerosis (ALS), a devastating, late-onset motor neuronal disease, with more than 150 ALS-related mutations in the SOD1 gene. Importantly, oxidatively damaged SOD1 aggregates have been observed in both familial and sporadic forms of the disease. However, the molecular mechanisms as well as potential implications of oxidative stress in SOD1-induced cytotoxicity remain elusive. In this study, we examine the effects of oxidative modification on SOD1 monomer and homodimer stability, the key molecular properties related to SOD1 aggregation. We use molecular dynamics simulations in combination with thermodynamic integration to study microscopic-level site-specific effects of oxidative "mutations" at the dimer interface, including lysine, arginine, proline and threonine carbonylation, and cysteine oxidation. Our results show that oxidative damage of even single residues at the interface may drastically destabilize the SOD1 homodimer, with several modifications exhibiting a comparable effect to that of the most drastic ALS-causing mutations known. Additionally, we show that the SOD1 monomer stability decreases upon oxidative stress, which may lead to partial local unfolding and consequently to increased aggregation propensity. Importantly, these results suggest that oxidative stress may play a key role in development of ALS, with the mutations in the SOD1 gene being an additional factor.
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Drazen
authors.initials: D
authors.lastname: Petrov
authors.affiliation: Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Daura
authors.affiliation: Department of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna, Austria. Electronic address: bojan.zagrovic@univie.ac.at.
authors.forename: Bojan
authors.initials: B
authors.lastname: Zagrovic
mesh_terms: D004795:Enzyme Stability; D006801:Humans; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D000072105:Superoxide Dismutase-1 / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D000072105:Superoxide Dismutase-1