Mia40 Combines Thiol Oxidase and Disulfide Isomerase Activity to Efficiently Catalyze Oxidative Folding in Mitochondria |
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| Institution: | 1. Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA;2. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA;1. Laboratoire d''Ingénierie des Systèmes Macromoléculaires, UMR 7255, Centre National de la Recherche Scientifique and Aix-Marseille University, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France;2. INSERM U 1109 and University of Strasbourg, 3 Avenue Molière, 67200 Strasbourg, France;1. Department of Physics, University of California at San Diego, La Jolla, CA 92093, USA;2. Department of NanoEngineering, University of California at San Diego, La Jolla, CA 92093, USA;1. Waksman Institute of Microbiology, Rutgers, The State University of New Jersey, NJ 08854, USA;2. Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA;3. Public Health Research Institute Center, New Jersey Medical School, Department of Microbiology and Molecular Genetics, University of Medicine and Dentistry of New Jersey, NJ 07103, USA;4. Department of Biochemistry and Molecular Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA;5. Institutes of Gene Biology and Molecular Genetics, Russian Academy of Sciences, Leninsky Avenue, 14, 119991 Moscow, Russia;1. Department of Molecular Biology, University of Bergen, Postbox 7803, 5020 Bergen, Norway;2. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, United Kingdom;3. Centre for Applied Biotechnology, Uni Research, Postbox 7810, 5020 Bergen, Norway;4. Faculty of Medicine and Dentistry, University of Bergen, Haukelandsveien 28, 5020 Bergen, Norway;5. Institute of Molecular Biotechnology (IMBA), Dr. Bohr-Gasse 3, 1030 Vienna, Austria |
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| Abstract: | Mia40 (a mitochondrial import and assembly protein) catalyzes disulfide bond formation in proteins in the mitochondrial intermembrane space. By using Cox17 (a mitochondrial copper-binding protein) as a natural substrate, we discovered that, in the presence of Mia40, the formation of native disulfides is strongly favored. The catalytic mechanism of Mia40 involves a functional interplay between the chaperone site and the catalytic disulfide. Mia40 forms a specific native disulfide in Cox17 much more rapidly than other disulfides, in particular, non-native ones, which originates from the recently described high affinity for hydrophobic regions near target cysteines and the long lifetime of the mixed disulfide. In addition to its thiol oxidase function, Mia40 is active also as a disulfide reductase and isomerase. We found that species with inadvertently formed incorrect disulfides are rebound by Mia40 and reshuffled, revealing a proofreading mechanism that is steered by the conformational folding of the substrate protein. |
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