1. MIA40 is an oxidoreductase that catalyzes oxidative protein folding in mitochondria
- Author
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Lucia Banci, Kostas Tokatlidis, Chiara Cefaro, Dionisia P. Sideris, Ivano Bertini, Nitsa Katrakili, Manuele Martinelli, Simone Ciofi-Baffoni, and Angelo Gallo
- Subjects
Models, Molecular ,Protein Folding ,Protein Conformation ,Mitochondrial intermembrane space ,NMR STRUCTURE DETERMINATION ,Molecular Sequence Data ,education ,Oxidative phosphorylation ,Protein degradation ,Mitochondrion ,Biology ,Thioredoxin fold ,RELAY SYSTEM ,Mitochondrial Membrane Transport Proteins ,CYTOCHROME-C ,Structural Biology ,Oxidoreductase ,Mitochondrial Precursor Protein Import Complex Proteins ,IMPORT PATHWAY ,Humans ,Amino Acid Sequence ,Nuclear Magnetic Resonance, Biomolecular ,Molecular Biology ,CHAPERONE ,chemistry.chemical_classification ,ERV1 ,Mitochondria ,INTERMEMBRANE SPACE PROTEINS ,DISULFIDE BOND FORMATION ,RESPIRATORY-CHAIN ,CHEMICAL-SHIFTS ,Biochemistry ,chemistry ,Protein folding ,Oxidation-Reduction ,Sequence Alignment ,Cysteine - Abstract
MIA40 has a key role in oxidative protein folding in the mitochondrial intermembrane space. We present the solution structure of human MIA40 and its mechanism as a catalyst of oxidative folding. MIA40 has a 66-residue folded domain made of an alpha-helical hairpin core stabilized by two structural disulfides and a rigid N-terminal lid, with a characteristic CPC motif that can donate its disulfide bond to substrates. The CPC active site is solvent-accessible and sits adjacent to a hydrophobic cleft. Its second cysteine (Cys55) is essential in vivo and is crucial for mixed disulfide formation with the substrate. The hydrophobic cleft functions as a substrate binding domain, and mutations of this domain are lethal in vivo and abrogate binding in vitro. MIA40 represents a thioredoxin-unrelated, minimal oxidoreductase, with a facile CPC redox active site that ensures its catalytic function in oxidative folding in mitochondria.
- Published
- 2009
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