title: MIA40 is an oxidoreductase that catalyzes oxidative protein folding in mitochondria.
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.
authors.affiliation: Magnetic Resonance Center CERM, University of Florence, Via Luigi Sacconi 6, 50019, Sesto Fiorentino, Florence, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Banci
authors.forename: Ivano
authors.initials: I
authors.lastname: Bertini
authors.forename: Chiara
authors.initials: C
authors.lastname: Cefaro
authors.forename: Simone
authors.initials: S
authors.lastname: Ciofi-Baffoni
authors.forename: Angelo
authors.initials: A
authors.lastname: Gallo
authors.forename: Manuele
authors.initials: M
authors.lastname: Martinelli
authors.forename: Dionisia P
authors.initials: DP
authors.lastname: Sideris
authors.forename: Nitsa
authors.initials: N
authors.lastname: Katrakili
authors.forename: Kostas
authors.initials: K
authors.lastname: Tokatlidis
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D011487:Protein Conformation; D017510:Protein Folding; D016415:Sequence Alignment
chemical_list: C507282:CHCHD4 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins