| 1988 |
Yeast SCO1 is required for a post-transcriptional step in the accumulation of mitochondrially synthesized cytochrome c oxidase subunit II (CoxII); Northern blot showed normal transcription/mRNA maturation of OXI1, but CoxII protein was strongly reduced in sco1-1 mutant, indicating SCO1 acts post-transcriptionally. |
Yeast genetic analysis, mitochondrial translation product analysis, Northern blot hybridization |
Molecular & general genetics : MGG |
Medium |
2835635
|
| 1989 |
Yeast SCO1 encodes a 33 kDa protein that is imported into mitochondria and processed to a 30 kDa form tightly associated with the mitochondrial membrane, as shown by in vitro transcription/translation and mitochondrial import assays. |
In vitro transcription/translation, mitochondrial import assay, protease protection |
Molecular & general genetics : MGG |
Medium |
2543907
|
| 1990 |
SCO1 protein is required for a post-translational step: SCO1-deleted yeast translates CoxI and CoxII normally but the newly synthesized subunits are preferentially degraded, indicating SCO1 protects them from proteolysis during assembly. |
Yeast genetics, pulse-chase labeling of mitochondrial translation products |
Current genetics |
Medium |
2173976
|
| 1991 |
Yeast SCO1 protein localizes to the inner mitochondrial membrane as an integral membrane protein; membrane localization is mediated by a 17-amino-acid hydrophobic N-terminal segment, and removal of this segment abolishes both membrane binding and biological function. |
Subcellular fractionation, alkaline extraction, isopycnic sucrose gradient centrifugation, digitonin treatment, immunoblot with anti-SCO1 antibodies |
Molecular & general genetics : MGG |
High |
1944230
|
| 1996 |
SCO1 and SCO2 act as high-copy suppressors of a COX17 copper-recruitment defect in yeast; SCO1 overexpression compensates for the absence of Cox17p, placing SCO1 downstream of COX17 in the mitochondrial copper delivery pathway to cytochrome c oxidase. SCO2 cannot suppress a sco1 null mutant, indicating non-identical functions. |
Yeast multicopy suppressor screen, genetic epistasis, null mutant complementation |
The Journal of biological chemistry |
High |
8702795
|
| 1998 |
Human SCO1 is the ortholog of yeast SCO1; the human protein contains conserved functional domains and is imported into mitochondria as shown by in vitro import and protease-protection assays. |
Sequence alignment, in vitro mitochondrial import assay, protease-protection assay |
Genomics |
Medium |
9878253
|
| 1999 |
Both human SCO1 homologs (chromosomes 17 and 22) localize to mitochondria in HeLa cells when expressed as EGFP fusions; a chimera of the N-terminal half of yeast Sco1p and the C-terminal half of human chromosome-17 SCO1 complements the yeast sco1 deletion, but neither full-length human protein alone does. |
EGFP fusion live-cell imaging, yeast complementation assay with chimeric proteins |
FEBS letters |
Medium |
10218584
|
| 2000 |
Pathogenic mutations in human SCO1 (2-bp frameshift and P174L missense in the conserved CxxxC copper-binding domain) cause isolated COX deficiency; the P174L mutation affects a conserved proline adjacent to the CxxxC copper-binding domain, likely disrupting its tertiary structure. |
Mutation screening, compound heterozygosity analysis, sequence conservation analysis |
American journal of human genetics |
Medium |
11013136
|
| 2001 |
Purified C-terminal domain of yeast Sco1 binds one Cu(I) per monomer via three ligands—two conserved cysteines in the CXXXC motif and a conserved histidine—as shown by X-ray absorption spectroscopy. Mutation of any one of these residues abolishes Sco1 function in yeast. |
Protein purification, X-ray absorption spectroscopy (XAS/EXAFS), site-directed mutagenesis, yeast functional assay |
The Journal of biological chemistry |
High |
11546815
|
| 2003 |
Solution structure of Sco1 from Bacillus subtilis (NMR) reveals a thioredoxin-like fold with the copper-binding CXXXCP motif positioned analogously to the catalytic residues in thioredoxins; in vitro binding shows Cu(I) coordinated through CXXXCP and His135, and Cu(II) binding also occurs but appears adventitious. |
NMR structure determination, in vitro copper binding |
Structure (London, England : 1993) |
High |
14604533
|
| 2003 |
In SCO1-deficient patient fibroblasts, a COX subassembly containing MTCO1, COX4, and COX5A accumulates, indicating that SCO1 function is required for the subsequent association of MTCO2 with this subassembly (i.e., Cu(A) center formation in MTCO2 precedes MTCO2 incorporation into the assembly line). |
Blue native gel electrophoresis, immunoblot of COX subassemblies from patient fibroblasts |
The Journal of biological chemistry |
Medium |
14607829
|
| 2004 |
Cox17 directly and specifically transfers Cu(I) to both Sco1 and Cox11 in vitro using purified proteins; a C57Y mutant of Cox17 fails to transfer copper to Sco1 but retains ability to transfer to Cox11, demonstrating distinct transfer mechanisms. Metallation of cytoplasmic Sco1 in yeast is strictly dependent on co-expression of Cox17. |
In vitro copper transfer assay with purified proteins, yeast cytoplasmic expression system, Cox17 mutagenesis |
The Journal of biological chemistry |
High |
15199057
|
| 2004 |
Human SCO1 and SCO2 have non-overlapping cooperative functions: COX17 overexpression rescues COX deficiency in SCO2 but not SCO1 patient cells; overexpression of either SCO protein in the reciprocal patient background produces a dominant-negative phenotype suggesting physical interaction. SCO1 and SCO2 function as homodimers by size-exclusion chromatography. The dominant-negative effect in SCO2 background maps to the N-terminal domain of SCO1. |
Patient cell lines, overexpression rescue/dominant-negative assays, chimeric protein complementation, size-exclusion chromatography |
Human molecular genetics |
High |
15229189
|
| 2005 |
Human Sco1 and Sco2 each bind Cu(I) (trigonal coordination) and Cu(II) (type II-like, higher coordination); Cu(I) binding requires two conserved cysteines and a histidine. Asp238 in human Sco1 is required for Cu(II) binding and normal in vivo function. Metallation of human Sco1 in yeast cytoplasm depends on co-expression of human Cox17, but Sco2 metallation does not. |
Protein expression in bacteria and yeast, X-ray absorption spectroscopy, site-directed mutagenesis, yeast functional assay |
The Journal of biological chemistry |
High |
16091356
|
| 2005 |
Crystal structure of human SCO1 (apo form, 2.8 Å) reveals a thioredoxin/peroxiredoxin-like fold with putative copper-binding ligands at positions equivalent to catalytic residues in Trx/Prx; SCO1 does not possess disulfide isomerization or peroxidase activity, but both human SCO1 and yeast sco1 null show extreme sensitivity to H2O2. |
X-ray crystallography, enzymatic activity assays (disulfide isomerization, peroxidase), H2O2 sensitivity assays |
The Journal of biological chemistry |
High |
15659396
|
| 2006 |
Solution structures of apo, Cu(I), and Ni(II) forms of human Sco1 (NMR) reveal that metal binding shifts the protein from an open, conformationally mobile state to a closed, rigid conformation. Cu(I) is coordinated by two Cys of the CPXXCP motif and a His residue. The Ni(II)-bound structure suggests the protein may also retain thioredoxin-like function in oxidized form. |
NMR structure determination, electrospray ionization mass spectrometry, X-ray crystallography of Ni(II) form |
Proceedings of the National Academy of Sciences of the United States of America |
High |
16735468
|
| 2006 |
Crystal structures of yeast apo-Sco1 (1.8 Å) and Cu-Sco1 (2.3 Å) show a thioredoxin-like fold; the conserved His239 is on a flexible 'Sco loop' proximal to both cysteine pairs; an unexpected copper-binding site involving non-conserved Cys181/Cys216 is observed in the soaked crystal. Electrostatic surface analysis suggests interaction sites with Cox17 and COX2. |
X-ray crystallography, copper soaking experiments |
Journal of biological inorganic chemistry |
High |
16570183
|
| 2006 |
The P174L pathogenic mutation of human Sco1 reduces Cu(I) binding affinity ~10,000-fold (KD ~10^-13 vs ~10^-17 M for wild-type), and impairs the transient Cox17/Cu(I)/Sco1 complex formation and copper transfer from Cu(I)Cox17 to Sco1, without abolishing copper binding entirely. |
NMR solution structure of mutant, Cu(I) affinity measurements, in vitro copper transfer assays, Cox17 interaction studies |
Proceedings of the National Academy of Sciences of the United States of America |
High |
17182746
|
| 2006 |
The P174L mutation in human Sco1 retains normal Cu(I) and Cu(II) binding when expressed in bacteria, but Cox17-mediated copper transfer to Sco1 is severely compromised both in vitro and in a yeast cytoplasmic assay. Pulse-chase labeling in SCO1 patient fibroblasts shows normal CoxII translation rate but rapid and specific turnover of newly synthesized CoxII. |
Protein expression and metal binding analysis, in vitro copper transfer assay, yeast cytoplasmic assay, pulse-chase labeling in patient fibroblasts |
The Journal of biological chemistry |
High |
16520371
|
| 2007 |
Human SCO1 and SCO2 have additional roles in cellular copper homeostasis beyond COX assembly; mutations in either SCO result in tissue- and allele-specific cellular copper deficiency that can be dissociated from COX assembly defects. The copper deficiency reflects increased copper efflux, not decreased uptake, and is suppressed by SCO2 overexpression but not SCO1 overexpression. |
Patient cell lines, shRNA knockdown, copper efflux/uptake measurements, SCO overexpression rescue |
Cell metabolism |
High |
17189203
|
| 2008 |
Cu(I)HCox17 (partially oxidized, 2S-S form) simultaneously transfers Cu(I) and two electrons to oxidized HSco1 (disulfide form), yielding Cu(I)HSco1 and fully oxidized apoHCox17; the reaction is thermodynamically driven by copper transfer. This coupled copper-electron transfer does not occur with HSco2 due to absence of a specific metal-bridged protein-protein complex. |
In vitro reconstitution with purified proteins, redox chemistry, NMR, thermodynamic analysis |
Proceedings of the National Academy of Sciences of the United States of America |
High |
18458339
|
| 2009 |
SCO2 acts upstream of SCO1 in COX assembly: pulse-labeling shows COX II synthesis is reduced in SCO2 but not SCO1 patient cells; RNAi of mutant SCO2 abolishes COX II labeling. SCO2 acts as a thiol-disulfide oxidoreductase to oxidize the copper-coordinating cysteines in SCO1 during COX II maturation; the ratio of oxidized to reduced cysteines in SCO1 is perturbed in both SCO patient backgrounds and is corrected by SCO2 overexpression or knockdown. |
Mitochondrial translation pulse-labeling, RNAi knockdown, cysteine redox state analysis in patient fibroblasts, overexpression rescue |
Human molecular genetics |
High |
19336478
|
| 2009 |
A fraction of Sco1 physically associates with the assembled COX complex in human muscle mitochondria as shown by blue native immunoblot and co-immunoprecipitation. The G132S mutation in SCO1 causes the protein to migrate exclusively as a monomer rather than a higher-order form, indicating the mutation disrupts oligomerization. |
Blue native gel electrophoresis, co-immunoprecipitation from human muscle mitochondria |
American journal of physiology. Cell physiology |
Medium |
19295170
|
| 2011 |
Despite global copper deficiency at the whole-cell level in SCO1 and SCO2 patient fibroblasts, total and exchangeable mitochondrial Cu(+) pools are largely maintained at normal levels, demonstrating that cells prioritize mitochondrial copper homeostasis even when SCO metallochaperones are dysfunctional. |
Fluorescent mitochondria-targeted copper sensor (Mito-CS1) live imaging, biochemical copper measurements in patient fibroblasts |
Journal of the American Chemical Society |
Medium |
21563821
|
| 2014 |
COX20 interacts with newly synthesized COX2, and SCO1 and SCO2 act on COX20-bound COX2; COX20 acts as a chaperone stabilizing newly synthesized COX2 and presenting it to the SCO1/SCO2 metallochaperone module for Cu(A) site maturation prior to COX2 incorporation into early COX subassemblies. |
siRNA knockdown, TALEN knockout, immunoprecipitation of COX20-FLAG with newly synthesized COX2, subassembly analysis |
Human molecular genetics |
High |
24403053
|
| 2015 |
SCO1 is required to maintain CTR1 (the high-affinity copper importer) protein at steady-state levels; in Sco1-/- mouse embryonic fibroblasts, CTR1 is rapidly degraded and its levels are restored by proteasome inhibition, establishing a post-translational mitochondrial-to-plasma-membrane signaling axis through SCO1 that regulates cellular copper import. |
Liver-specific Sco1 knockout mice, immunoblot, proteasome inhibitor treatment in MEFs |
Cell reports |
High |
25683716
|
| 2017 |
In the heart, SCO1 maintains CTR1 at the plasma membrane; cardiac-specific and striated-muscle-specific Sco1 deletion causes dilated cardiomyopathy with combined COX and copper deficiency, and CTR1 is mislocalised to the cytosol rather than degraded (unlike in liver), demonstrating tissue-specific consequences of SCO1 loss on CTR1 regulation. |
Heart- and striated-muscle-specific Sco1 knockout and knockin (G115S) mice, immunofluorescence for CTR1 localization, COX activity assays, copper measurements |
Human molecular genetics |
High |
28973536
|
| 2017 |
SCO1 overexpression in adipocytes leads to intracellular copper deficiency, and this copper loss causes insulin resistance by increasing PTEN protein levels; addition of exogenous copper abolishes the insulin resistance caused by SCO1 overexpression, establishing SCO1 as a regulator of insulin sensitivity via copper levels in white adipose tissue. |
Overexpression in adipocytes, copper supplementation rescue, PTEN protein measurement, insulin sensitivity assays |
Biochemical and biophysical research communications |
Low |
28647369
|
| 2022 |
Copper-loaded SCO1 directly interacts with LKB1 and tethers LKB1 to AMPK, thereby activating AMPK and promoting mitochondrial biogenesis and fatty acid oxidation; SCO1 constitutively interacts with LKB1 even without copper, but copper loading is required for AMPK tethering and activation. |
Co-immunoprecipitation, SCO1 knockout and overexpression in mice and cells, AMPK activity assays, copper restoration experiments |
Cell reports |
Medium |
36261001
|
| 2025 |
In an isogenic murine background, the heart is the most susceptible organ to SCO1 loss-of-function; Sco1G115S and Sco1P157L knockin hearts develop dilated cardiomyopathy with combined COX and copper deficiency including mitochondrial copper pool depletion, while brain-specific Sco1 knockout causes severe COX deficiency without altered copper content, demonstrating tissue-specific mechanisms of SCO1 function. |
Brain-specific Sco1 knockout mice, whole-body SCO1 knockin mice (G115S, P157L, M277V), COX activity assays, copper content measurements (including mitochondrial copper pool) |
Human molecular genetics |
High |
40679281
|