Abstract
The heterodimerization of wild-type (WT) Cu, Zn superoxide dismutase-1 (SOD1) and mutant SOD1 might be a critical step in the pathogenesis of SOD1-linked amyotrophic lateral sclerosis (ALS). Post-translational modifications that accelerate SOD1 heterodimerization remain unidentified. Here, we used capillary electrophoresis to quantify the effect of cysteine-111 oxidation on the rate and free energy of ALS mutant/WT SOD1 heterodimerization. The oxidation of Cys111-β-SH to sulfinic and sulfonic acid (by hydrogen peroxide) increased rates of heterodimerization (with unoxidized protein) by ∼3-fold. Cysteine oxidation drove the equilibrium free energy of SOD1 heterodimerization by up to ΔΔG = -5.11 ± 0.36 kJ mol-1. Molecular dynamics simulations suggested that this enhanced heterodimerization, between oxidized homodimers and unoxidized homodimers, was promoted by electrostatic repulsion between the two "dueling" Cys111-SO2-/SO3-, which point toward one another in the homodimeric state. Together, these results suggest that oxidation of Cys-111 promotes subunit exchange between oxidized homodimers and unoxidized homodimers, regardless of whether they are mutant or WT dimers.
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