title: A human SCO2 mutation helps define the role of Sco1p in the cytochrome oxidase assembly pathway.
abstract: Deficiencies in cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain, are most often caused by an inability to complete assembly of the enzyme. Pathogenic mutations in SCO2, which encodes a cytochrome oxidase assembly factor, were recently described in several cases of fatal infantile cardioencephalomyopathy. To determine the molecular etiology of these disorders, we describe the generation and characterization of the parallel mutations in the homologous yeast SCO1 gene. We show that the E155K yeast sco1 mutant is respiration-competent, whereas the S240F mutant is not. Interestingly, the S240F mutation allows partial but incorrect assembly of cytochrome oxidase, as judged by an altered cytochrome aa(3) peak. Immunoblot analysis reveals a specific absence of subunit 2 from the cytochrome oxidase in this mutant. Taken together, our data suggest that Sco1p provides copper to the Cu(A) site on subunit 2 at a step occurring late in the assembly pathway. This is the first instance of a yeast cytochrome oxidase assembly mutant that is partially assembled. The S240F mutant also represents a powerful new tool with which to elucidate further steps in the cytochrome oxidase assembly pathway.
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
authors.forename: E K
authors.initials: EK
authors.lastname: Dickinson
authors.forename: D L
authors.initials: DL
authors.lastname: Adams
authors.forename: E A
authors.initials: EA
authors.lastname: Schon
authors.forename: D M
authors.initials: DM
authors.lastname: Glerum
mesh_terms: D002352:Carrier Proteins; D020134:Catalytic Domain; D003576:Electron Transport Complex IV / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D011506:Proteins; C489345:SCO1 protein, human; C498516:SCO2 protein, S cerevisiae; C400285:SCO2 protein, human; D029701:Saccharomyces cerevisiae Proteins; D003576:Electron Transport Complex IV