title: The mitochondrial intermembrane space oxireductase Mia40 funnels the oxidative folding pathway of the cytochrome c oxidase assembly protein Cox19.
abstract: Mia40-catalyzed disulfide formation drives the import of many proteins into the mitochondria. Here we characterize the oxidative folding of Cox19, a twin CX9C Mia40 substrate. Cox19 oxidation is extremely slow, explaining the persistence of import-competent reduced species in the cytosol. Mia40 accelerates Cox19 folding through the specific recognition of the third Cys in the second helical CX9C motif and the subsequent oxidation of the inner disulfide bond. This renders a native-like intermediate that oxidizes in a slow uncatalyzed reaction into native Cox19. The same intermediate dominates the pathway in the absence of Mia40, and chemical induction of an α-helical structure by trifluoroethanol suffices to accelerate productive folding and mimic the Mia40 folding template mechanism. The Mia40 role is to funnel a rough folding landscape, skipping the accumulation of kinetic traps, providing a rationale for the promiscuity of Mia40.
authors.affiliation: From the Institut de Biotecnologia i Biomedicina and.
authors.forename: Hugo
authors.initials: H
authors.lastname: Fraga
authors.forename: Joan-Josep
authors.initials: JJ
authors.lastname: Bech-Serra
authors.forename: Francesc
authors.initials: F
authors.lastname: Canals
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ortega
authors.forename: Oscar
authors.initials: O
authors.lastname: Millet
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
mesh_terms: D020816:Amino Acid Motifs; D001693:Biological Transport, Active / Q000502:physiology; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008928:Mitochondria / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C520018:Cox19 protein, S cerevisiae; D004220:Disulfides; C495320:MIA40 protein, S cerevisiae; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D018832:Molecular Chaperones; D029701:Saccharomyces cerevisiae Proteins
keywords: Biophysics; Cox19; Disulfide; Mia40; Mitochondria; Oxidation-Reduction; Protein Folding; Protein Oxidative Folding; Protein Translocation