Human members of the <i>SCO1</i> gene family: complementation analysis in yeast and intracellular localization

Paret, Claudia; Ostermann, Kai; Krause‐Buchholz, Udo; Rentzsch, Anja; Rödel, Gerhard

doi:10.1016/s0014-5793(99)00266-5

Cited by 45 publications

(32 citation statements)

References 24 publications

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“…In the human genome two genes have been identified, hSCO1 located on chromosome 17p12-13 and hSCO2 on chromosome 22q13. Both encode mt proteins (Petruzzella et al, 1998;Paret et al, 1999), which are essential for mt function as shown by the recent detection of mutations associated with fatal COX deficiencies. Mutations in hSCO2 were reported in infants who suffered from a fatal disorder with hypertrophic cardiomyopathy as the predominant symptom (Papadopoulou et al, 1999;Jaksch et al, 2000Jaksch et al, , 2001a whereas the key symptoms of the infant patients carrying mutations in the hSCO1 gene were hepatic failure and ketoacidotic coma (Valnot et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of Saccharomyces cerevisiae Sco2p reveals a high degree of redundancy with Sco1p

Lode¹,

Paret²,

Rödel³

2002

Yeast

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The Saccharomyces cerevisiae gene SCO1 has been shown to play an essential role in the transfer of copper to the Cu A -centre of the mitochondrial cytochrome c oxidase subunit Cox2p. By contrast, the function of Sco2p, the gene product of the highly homologous SCO2 gene, remains to be elucidated. Deletion of the SCO2 gene does not affect growth on a variety of carbon sources, including glycerol, lactate and ethanol. We report here, that Sco2p is anchored in the mitochondrial membrane by a single transmembrane segment and displays a similar tripartite structure as Sco1p. Most parts of Sco1p can be replaced by the homologous parts of Sco2p without loss of function. A short stretch of 13 amino acids, immediately adjacent to the transmembrane region, is crucial for Sco1p function and cannot be replaced by its Sco2p counterpart. We propose that this region is relevant for the correct spatial orientation of the C-terminal part of the protein. Immunoprecipitation and in vitro binding assays show that Sco2p interacts with the C-terminal portion of Cox2p. This interaction is neither dependent on bound copper ions nor on the presence of Sco1p. Furthermore we report on in vitro binding assays which show that Sco2p can form homomeric complexes, but also heteromeric complexes with Sco1p. Our data suggest that Sco2p is involved in the transfer of copper to Cox2p, but that this activity is insufficient for oxidative growth and not able to substitute for Sco1p activity.

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Section: Introductionmentioning

confidence: 99%

Molecular characterization of Saccharomyces cerevisiae Sco2p reveals a high degree of redundancy with Sco1p

Lode¹,

Paret²,

Rödel³

2002

Yeast

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“…Like SURF1, SCO1 and SCO2 are mitochondrial inner membrane proteins (21)(22)(23). SCO proteins have a conserved CXXXC motif protruding into the intermembrane space, similar to the CXXXC motif present at the Cu A site of MTCO2 (24).…”

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confidence: 99%

Cytochrome c Oxidase Subassemblies in Fibroblast Cultures from Patients Carrying Mutations in COX10, SCO1, or SURF1

Williams

Valnot

Rustin

et al. 2004

Journal of Biological Chemistry

127

135

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Cytochrome c oxidase contains two redox-active copper centers (Cu A and Cu B ) and two redox-active heme A moieties. Assembly of the enzyme relies on several assembly factors in addition to the constituent subunits and prosthetic groups. We studied fibroblast cultures from patients carrying mutations in the assembly factors COX10, SCO1, or SURF1. COX10 is involved in heme A biosynthesis. SCO1 is required for formation of the Cu A center. The function of SURF1 is unknown. Immunoblot analysis of native gels demonstrated severely decreased levels of holoenzyme in the patient cultures compared with controls. In addition, the blots revealed the presence of five subassemblies: three subassemblies involving the core subunit MTCO1 but apparently no other subunits; a subassembly containing subunits MTCO1, COX4, and COX5A; and a subassembly containing at least subunits MTCO1, MTCO2, MTCO3, COX4, and COX5A. As some of the subassemblies correspond to known assembly intermediates of human cytochrome c oxidase, we think that these subassemblies are probably assembly intermediates that accumulate in patient cells. The MTCO1⅐COX4⅐COX5A subassembly was not detected in COX10-deficient cells, which suggests that heme A incorporation into MTCO1 occurs prior to association of MTCO1 with COX4 and COX5A. SCO1-deficient cells contained accumulated levels of the MTCO1⅐COX4⅐COX5A subassembly, suggesting that MTCO2 associates with the MTCO1⅐COX4⅐COX5A subassembly after the Cu A center of MTCO2 is formed. Assembly in SURF1-deficient cells appears to stall at the same stage as in SCO1-deficient cells, pointing to a role for SURF1 in promoting the association of MTCO2 with the MTCO1⅐COX4⅐COX5A subassembly.

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“…Human Sco1 and Sco2 are nonfunctional in yeast sco1⌬ cells (15). However, a chimeric protein consisting of 158 residues from the N terminus of yeast Sco1 fused to a C-terminal segment of hSco1, but not hSco2, is functional.…”

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confidence: 99%

“…However, a chimeric protein consisting of 158 residues from the N terminus of yeast Sco1 fused to a C-terminal segment of hSco1, but not hSco2, is functional. A P174L substitution was found to attenuate its function (15,16), although the CcO deficiency in yeast sco1⌬ cells harboring the mutant yeast/human Sco1 chimera could be rescued for growth on a nonfermentable carbon by the addition of 0.2% CuSO 4 (16). This suggests that P174L Sco1 retains some residual function; however, the molecular defect in Sco1 function that results from this amino acid substitution remains unknown.…”

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The P174L Mutation in Human Sco1 Severely Compromises Cox17-dependent Metallation but Does Not Impair Copper Binding

Cobine¹,

Pierrel²,

Leary³

et al. 2006

Journal of Biological Chemistry

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Sco1 is a metallochaperone that is required for copper delivery to the Cu A site in the CoxII subunit of cytochrome c oxidase. The only known missense mutation in human Sco1, a P174L substitution in the copper-binding domain, is associated with a fatal neonatal hepatopathy; however, the molecular basis for dysfunction of the protein is unknown. Immortalized fibroblasts from a SCO1 patient show a severe deficiency in cytochrome c oxidase activity that was partially rescued by overexpression of P174L Sco1. The mutant protein retained the ability to bind Cu(I) and Cu(II) normally when expressed in bacteria, but Cox17-mediated copper transfer was severely compromised both in vitro and in a yeast cytoplasmic assay. The corresponding P153L substitution in yeast Sco1 was impaired in suppressing the phenotype of cells harboring the weakly functional C57Y allele of Cox17; however, it was functional in sco1⌬ yeast when the wild-type COX17 gene was present. Pulse-chase labeling of mitochondrial translation products in SCO1 patient fibroblasts showed no change in the rate of CoxII translation, but there was a specific and rapid turnover of CoxII protein in the chase. These data indicate that the P174L mutation attenuates a transient interaction with Cox17 that is necessary for copper transfer. They further suggest that defective Cox17-mediated copper metallation of Sco1, as well as the subsequent failure of Cu A site maturation, is the basis for the inefficient assembly of the cytochrome c oxidase complex in SCO1 patients.

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Human members of the SCO1 gene family: complementation analysis in yeast and intracellular localization

Abstract: Cytochrome c oxidase is a multiprotein complex in the mitochondrial membrane whose biogenesis requires a number of proteins besides the structural subunits.

Cited by 45 publications

References 24 publications

Molecular characterization of Saccharomyces cerevisiae Sco2p reveals a high degree of redundancy with Sco1p

Molecular characterization of Saccharomyces cerevisiae Sco2p reveals a high degree of redundancy with Sco1p

Cytochrome c Oxidase Subassemblies in Fibroblast Cultures from Patients Carrying Mutations in COX10, SCO1, or SURF1

The P174L Mutation in Human Sco1 Severely Compromises Cox17-dependent Metallation but Does Not Impair Copper Binding

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