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PMID:21865594
| Citation |
Klöppel, C, Suzuki, Y, Kojer, K, Petrungaro, C, Longen, S, Fiedler, S, Keller, S and Riemer, J (2011) Mia40-dependent oxidation of cysteines in domain I of Ccs1 controls its distribution between mitochondria and the cytosol. Mol. Biol. Cell 22:3749-57 |
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| Abstract |
Superoxide dismutase 1 (Sod1) is an important antioxidative enzyme that converts superoxide anions to hydrogen peroxide and water. Active Sod1 is a homodimer containing one zinc ion, one copper ion, and one disulfide bond per subunit. Maturation of Sod1 depends on its copper chaperone (Ccs1). Sod1 and Ccs1 are dually localized proteins that reside in the cytosol and in the intermembrane space of mitochondria. The import of Ccs1 into mitochondria depends on the mitochondrial disulfide relay system. However, the exact mechanism of this import process has been unclear. In this study we detail the import and folding pathway of Ccs1 and characterize its interaction with the oxidoreductase of the mitochondrial disulfide relay Mia40. We identify cysteines at positions 27 and 64 in domain I of Ccs1 as critical for mitochondrial import and interaction with Mia40. On interaction with Mia40, these cysteines form a structural disulfide bond that stabilizes the overall fold of domain I. Although the cysteines are essential for the accumulation of functional Ccs1 in mitochondria, they are dispensable for the enzymatic activity of cytosolic Ccs1. We propose a model in which the Mia40-mediated oxidative folding of domain I controls the cellular distribution of Ccs1 and, consequently, active Sod1. |
| Links |
PubMed PMC3192855 Online version:10.1091/mbc.E11-04-0293 |
| Keywords |
Cloning, Molecular; Cysteine/chemistry; Cysteine/metabolism; Cytosol/metabolism; Disulfides/metabolism; Escherichia coli; Gene Expression Regulation, Fungal; Mitochondria/genetics; Mitochondria/metabolism; Mitochondrial Membrane Transport Proteins/genetics; Mitochondrial Membrane Transport Proteins/metabolism; Mitochondrial Membranes/metabolism; Molecular Chaperones/chemistry; Molecular Chaperones/genetics; Molecular Chaperones/metabolism; Mutation; Oxidation-Reduction; Plasmids; Protein Folding; Protein Transport/genetics; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae/metabolism; Saccharomyces cerevisiae Proteins/chemistry; Saccharomyces cerevisiae Proteins/genetics; Saccharomyces cerevisiae Proteins/metabolism; Signal Transduction/genetics; Superoxide Dismutase/genetics; Superoxide Dismutase/metabolism; Transduction, Genetic; Transformation, Bacterial |
| edit table |
Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0018316: peptide cross-linking via L-cystine |
ECO:0000315: |
P |
fig 2C: we found that the C27–C64 disulfide was formed in the presence of Mia40-WT. Of importance, in the absence of functional Mia40 no oxidation of the two cysteines occurred |
complete | ||||
| GO:0015677: copper ion import |
ECO:0000315: |
P |
fig. 1: copper chaperone for Sod1 (Ccs1) We identified two cysteines (Cys-27 and Cys-64) in domain I that are required for mitochondrial import of Ccs1—but not for its role in Sod1 maturation—by the use of cysteine mutants. |
complete | ||||
See also
References
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