Cu,Zn-superoxide dismutase without Zn is folded but catalytically inactive.
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Nedd S, Redler RL, Proctor EA, Dokholyan NV, Alexandrova AN
Cu,Zn-superoxide dismutase without Zn is folded but catalytically inactive.
J Mol Biol. 2014 Dec 12;426(24):4112-4124. doi: 10.1016/j.jmb.2014.07.016. Epub 2014 Jul 30.
- PubMed ID
- 25083917 [ View in PubMed]
- Abstract
Amyotrophic lateral sclerosis has been linked to the gain of aberrant function of superoxide dismutase, Cu,Zn-SOD1 upon protein misfolding. The mechanism of SOD1 misfolding is thought to involve mutations leading to the loss of Zn, followed by protein unfolding and aggregation. We show that the removal of Zn from SOD1 may not lead to an immediate unfolding but immediately deactivates the enzyme through a combination of subtle structural and electronic effects. Using quantum mechanics/discrete molecular dynamics, we showed that both Zn-less wild-type (WT)-SOD1 and its D124N mutant that does not bind Zn have at least metastable folded states. In those states, the reduction potential of Cu increases, leading to the presence of detectable amounts of Cu(I) instead of Cu(II) in the active site, as confirmed experimentally. The Cu(I) protein cannot participate in the catalytic Cu(I)-Cu(II) cycle. However, even without the full reduction to Cu(I), the Cu site in the Zn-less variants of SOD1 is shown to be catalytically incompetent: unable to bind superoxide in a way comparable to the WT-SOD1. The changes are more radical and different in the D124N Zn-less mutant than in the Zn-less WT-SOD1, suggesting D124N being perhaps not the most adequate model for Zn-less SOD1. Overall, Zn in SOD1 appears to be influencing the Cu site directly by adjusting its reduction potential and geometry. Thus, the role of Zn in SOD1 is not just structural, as was previously thought; it is a vital part of the catalytic machinery.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Zinc chloride Superoxide dismutase [Cu-Zn] Protein Humans UnknownCofactorDetails Zinc sulfate, unspecified form Superoxide dismutase [Cu-Zn] Protein Humans UnknownCofactorDetails