title: Mia40 is optimized for function in mitochondrial oxidative protein folding and import.
abstract: Mia40 catalyzes oxidative protein folding in mitochondria. It contains a unique catalytic CPC dithiol flanked by a hydrophobic groove, and unlike other oxidoreductases, it forms long-lived mixed disulfides with substrates. We show that this distinctive property originates neither from particular properties of mitochondrial substrates nor from the CPC motif of Mia40. The catalytic cysteines of Mia40 display unusually low chemical reactivity, as expressed in conventional pK values and reduction potentials. The stability of the mixed disulfide intermediate is coupled energetically with hydrophobic interactions between Mia40 and the substrate. Based on these properties, we suggest a mechanism for Mia40, where the hydrophobic binding site is employed to select a substrate thiol for forming the initial mixed disulfide. Its long lifetime is used to retain partially folded proteins in the mitochondria and to direct folding toward forming the native disulfide bonds.
authors: Laboratorium für Biochemie und Bayreuther Zentrum für Molekulare Biologie, Universität Bayreuth , 95440 Bayreuth, Germany.
authors: Johanna R
authors: JR
authors: Koch
authors: Franz X
authors: FX
authors: Schmid
mesh_terms: D020134:Catalytic Domain; D027682:Cation Transport Proteins / Q000737:chemistry / Q000378:metabolism; D000079922:Copper Transport Proteins; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry; D004228:Dithionitrobenzoic Acid / Q000737:chemistry / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D019704:Protein Disulfide-Isomerases / Q000737:chemistry / Q000378:metabolism; D017510:Protein Folding; D055550:Protein Stability; D021381:Protein Transport; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: C100359:COX17 protein, S cerevisiae; D027682:Cation Transport Proteins; D000079922:Copper Transport Proteins; D004220:Disulfides; D029968:Escherichia coli Proteins; C495320:MIA40 protein, S cerevisiae; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins; D004228:Dithionitrobenzoic Acid; D019704:Protein Disulfide-Isomerases; C526648:dsbA protein, E coli; D003545:Cysteine