Affinage

CCS

Copper chaperone for superoxide dismutase · UniProt O14618

Length
274 aa
Mass
29.0 kDa
Annotated
2026-06-09
100 papers in source corpus 21 papers cited in narrative 21 extracted findings
Cross-family judge faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCS is a copper chaperone that delivers copper to and catalyzes the maturation of the antioxidant enzyme SOD1 (PMID:9726962, PMID:15215895). It recognizes immature SOD1 through its SOD1-homologous domain II, which retains all zinc-binding ligands but substitutes Asp200 for one of the four copper-binding histidines, an evolutionary change that precludes deleterious copper chemistry within CCS itself (PMID:9726962, PMID:10601249). The copper-loaded form of CCS catalyzes the oxidative formation of SOD1's conserved intra-subunit disulfide bond, converting apo-SOD1 to the active enzyme in a strictly oxygen-dependent reaction; existing apo-SOD1 pools are activated by CCS early in the oxidative response prior to new protein synthesis (PMID:15215895, PMID:15064408). CCS acquires its copper from a cell-surface-derived intracellular pool, interacting with the cytosolic tail of the importer Ctr1 to form a Cu(I)-Ctr1·CCS·SOD1 transfer intermediate that disassembles only upon complete SOD1 activation, and it can also exchange copper bidirectionally with the cytosolic chaperone Atox1 (PMID:25673218, PMID:31292775). Beyond metal insertion, CCS acts as a molecular chaperone that stabilizes apo-SOD1, prevents accumulation of unstructured mutant protein, and promotes site-specific high-affinity zinc binding—a function independent of copper insertion (PMID:18337307, PMID:29234142, PMID:32121118). CCS additionally promotes SOD1 maturation and retention in the mitochondrial intermembrane space, where it is itself imported under control of the Mia40/Erv1 disulfide relay (PMID:11500508, PMID:20367259), and delivers copper to MEK1 to support its kinase activity (PMID:34715128). CCS activity is regulated by ubiquitination: XIAP-mediated ubiquitination enhances its chaperone function while TRIM22-mediated K27-linked ubiquitination at Lys76 targets it for proteasomal degradation, lowering ROS scavenging (PMID:20154138, PMID:39127340). A human domain II mutation, p.Arg163Trp, impairs SOD1 binding and constitutes the first pathogenic mutation identified in a copper chaperone gene, converting CCS into a copper-scavenging 'anti-chaperone' that accelerates SOD1 deactivation (PMID:22508683, PMID:39099176).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Established that CCS physically engages SOD1, defining the substrate-recognition basis of copper chaperone function and showing it also binds FALS mutant SOD1.

    Evidence Reciprocal Co-IP and in vitro binding with sequence alignment of homologous dimerization domains

    PMID:9726962

    Open questions at the time
    • Did not resolve whether binding alone or copper transfer drives SOD1 activation
    • Functional consequence for FALS mutant maturation not addressed
  2. 1999 High

    Defined the domain II SOD1-like architecture and explained why an Asp200 substitution for a copper-binding histidine prevents CCS from acquiring its own SOD activity.

    Evidence Site-directed mutagenesis (D200H) in yeast with SOD activity assays; companion homology modelling of three structural domains

    PMID:10467139 PMID:10601249

    Open questions at the time
    • Copper-transfer pathway from homology model lacks experimental structural validation
    • Domain-by-domain contribution to copper handling not dissected in vivo
  3. 2001 High

    Showed CCS levels govern SOD1 accumulation in the mitochondrial IMS, linking the chaperone to compartment-specific antioxidant protection.

    Evidence Subcellular fractionation with genetic CCS repression, protein carbonyl and survival assays in yeast

    PMID:11500508

    Open questions at the time
    • Mechanism of CCS mitochondrial import not yet defined
    • Relevance to mammalian IMS not tested here
  4. 2004 High

    Resolved the catalytic core of maturation—Cu-CCS oxidatively forms the SOD1 disulfide bond and this requires molecular oxygen, defining CCS as an O2-dependent disulfide-forming chaperone.

    Evidence In vitro reconstitution with purified proteins, redox-state and monomer-dimer analysis, plus O2-tension dose-response in cell extracts and translation-blocking experiments

    PMID:15064408 PMID:15215895

    Open questions at the time
    • Source of the oxidizing equivalent in vivo not fully defined
    • How CCS coordinates copper insertion with disulfide isomerization step-by-step unresolved
  5. 2004 High

    Identified a parallel CCS-independent, glutathione-dependent SOD1 activation route and the SOD1 sequence determinant that gates use of each pathway.

    Evidence Expression of human SOD1 in CCS-null yeast and mammalian cells, GSH depletion, and C-terminal proline mutagenesis

    PMID:15069187

    Open questions at the time
    • Physiological balance between CCS-dependent and -independent routes in human tissues unknown
  6. 2008 High

    Separated CCS's copper-insertion catalysis from a copper-independent molecular chaperone activity, and revealed that CCS overexpression is toxic in an ALS mouse model with respiratory-chain consequences.

    Evidence G93A/CCS transgenic mice with in vivo SOD1 disulfide redox analysis and detergent-solubility assays using a C244,246S CCS mutant; respiratory complex assays, BN-PAGE and heme A analysis of spinal cord

    PMID:18334481 PMID:18337307

    Open questions at the time
    • Mechanism linking CCS overexpression to isolated complex IV deficiency not established
    • How copper-insertion-independent chaperone activity prevents misfolding mechanistically unclear
  7. 2009 High

    Confirmed that disulfide oxidation by CCS strictly requires both copper and oxygen, while the alternative pathway can act anaerobically, and pinpointed a SOD1 proline dictating the requirement.

    Evidence Yeast expression under anaerobic and copper-depleted conditions with SOD1 proline mutagenesis and activity assays

    PMID:19542232

    Open questions at the time
    • Identity of the in vivo electron acceptor not defined
    • Mammalian counterpart of the proline determinant not tested
  8. 2010 Medium

    Integrated CCS into the Mia40/Erv1 disulfide relay, explaining redox-dependent control of CCS mitochondrial import and downstream SOD1 IMS retention.

    Evidence Review synthesis of fractionation and genetic analyses in yeast and mammalian cells

    PMID:20367259

    Open questions at the time
    • Review-level synthesis; individual experiments not detailed here
    • Direct CCS-Mia40 contact sites not mapped
  9. 2010 High

    Revealed regulatory ubiquitination of CCS by XIAP that enhances rather than degrades, and bidirectional copper delivery from CCS to XIAP.

    Evidence Reciprocal Co-IP, ubiquitination assays, and SOD1 activity readouts with XIAP manipulation in cells

    PMID:20154138

    Open questions at the time
    • Ubiquitin linkage type and CCS acceptor residue not defined
    • How ubiquitination mechanistically boosts chaperone activity unknown
  10. 2012 High

    Identified the first human pathogenic mutation in a copper chaperone gene, tying CCS dysfunction to disease through impaired SOD1 binding.

    Evidence Immunoprecipitation, patient fibroblast biochemistry, and yeast complementation of the R163W variant

    PMID:22508683

    Open questions at the time
    • Clinical spectrum and penetrance not established by a single case
    • Molecular basis of the binding defect not yet resolved here
  11. 2015 Medium

    Demonstrated cross-pathway copper exchange between CCS domain I and the cytosolic chaperone Atox1, situating CCS within the broader copper-trafficking network.

    Evidence NMR, size-exclusion chromatography copper-loading readouts, and Cys→Ala mutagenesis of Atox1 in vitro

    PMID:25673218

    Open questions at the time
    • In vitro only; cellular relevance of Atox1-CCS exchange untested
    • Directionality control in vivo unknown
  12. 2017 High

    Provided structural in-cell evidence that CCS domain II stabilizes apo/mutant SOD1 and promotes zinc binding, formalizing a chaperone role distinct from copper insertion; also discovered S-acylation and an ultrastable SOD1-CCS heterodimer in spinal cord.

    Evidence In-cell and in vitro NMR with SOD1 mutants; acyl-RAC across human/mouse spinal cord plus cysteine mutagenesis in HEK293 cells

    PMID:28120938 PMID:29234142

    Open questions at the time
    • Enzyme catalyzing CCS S-acylation not identified
    • Physiological role of the ultrastable heterodimer unresolved
  13. 2019 High

    Reconstituted the copper hand-off from Ctr1 to CCS to SOD1, showing a tripartite transfer intermediate that disassembles only when SOD1 is fully activated.

    Evidence In vitro reconstitution and pulldown/co-elution with purified Ctr1 cytosolic tail, CCS, and engineered immature SOD1

    PMID:31292775

    Open questions at the time
    • Cellular validation of the heterotrimer not shown
    • Kinetics of complex assembly/disassembly not quantified
  14. 2020 Medium

    Showed CCS-promoted high-affinity zinc binding is disrupted by diverse fALS SOD1 mutations, proposing nonproductive maturation as a shared disease link.

    Evidence Zinc affinity measurements of wild-type and fALS SOD1 mutants ± CCS

    PMID:32121118

    Open questions at the time
    • Single primary method (affinity measurement) from one lab
    • Causal link to aggregation/toxicity in vivo not demonstrated
  15. 2021 High

    Extended CCS copper delivery beyond SOD1 to MEK1, connecting the chaperone to MAPK signaling.

    Evidence SPR binding, BioID proximity labeling, CCS Cu-binding mutants and a small-molecule inhibitor with MEK1 kinase assays

    PMID:34715128

    Open questions at the time
    • Structural basis of CCS-MEK1 copper transfer not resolved
    • Physiological signaling contexts requiring CCS-MEK1 not defined
  16. 2024 High

    Defined a second regulatory ubiquitination axis (TRIM22 K27-linked at Lys76) driving CCS degradation with consequences for ROS and STAT3 signaling, and mechanistically explained R163W as an anti-chaperone.

    Evidence Proteomics, Co-IP, ubiquitination assays and mutagenesis (TRIM22 coiled-coil, CCS Lys76) with ROS/STAT3 readouts; comprehensive Cu(I)/Zn binding and disulfide analysis of R163W

    PMID:39099176 PMID:39127340

    Open questions at the time
    • Interplay between XIAP and TRIM22 ubiquitination of CCS unknown
    • Whether anti-chaperone mechanism generalizes to other domain II mutations untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CCS integrates its multiple roles—SOD1 maturation, mitochondrial IMS retention, MEK1 copper delivery, and opposing ubiquitin regulation—within a single cell, and how the in vivo oxidizing equivalent and import machinery are coordinated, remains unresolved.
  • No structure of a full Ctr1-CCS-SOD1 transfer complex in cells
  • Relative flux through CCS-dependent vs GSH-dependent SOD1 activation in human tissues unquantified
  • Mechanistic basis of CCS overexpression toxicity and complex IV deficiency unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140104 molecular carrier activity 4 GO:0044183 protein folding chaperone 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0016491 oxidoreductase activity 2
Localization
GO:0005739 mitochondrion 2 GO:0005829 cytosol 2
Pathway
GO:0140096 catalytic activity, acting on a protein 2
Partners
ATOX1CTR1MEK1SOD1TRIM22XIAP

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 CCS (copper chaperone for SOD1) directly interacts with SOD1 in vitro and in vivo, and this interaction is mediated via the homologous SOD1-like domain in CCS. CCS also interacts with FALS mutant forms of SOD1. Co-immunoprecipitation, in vitro binding assays, amino acid sequence alignment identifying homologous dimerization domains The Journal of biological chemistry High 9726962
1999 CCS domain II shares ~50% identity with SOD1 and contains all zinc-binding ligands but only three of four copper-binding histidines (the fourth is Asp200). A D200H mutation in CCS confers superoxide dismutase activity without abolishing copper chaperone function, indicating Asp200 evolved to preclude deleterious copper reactions in CCS. Site-directed mutagenesis of CCS expressed in yeast, SOD activity assays The Journal of biological chemistry High 10601249
1999 CCS contains three structural domains; a homology model based on bacterial mercury-detoxification proteins and SOD structure predicts a copper-transfer pathway involving sulfur ligands, accounting for electrostatic target recognition, copper storage, and transfer to SOD. Homology modelling of CCS three-dimensional structure Structure (London, England : 1993) Low 10467139
2001 A fraction of CCS and active SOD1 co-localizes to the mitochondrial intermembrane space (IMS) in yeast. Mitochondrial accumulation of SOD1 is strongly influenced by CCS: repression of CCS reduces IMS SOD1, while high mitochondrial CCS increases IMS SOD1. IMS SOD1 is protective against mitochondrial oxidative damage. Subcellular fractionation, genetic repression of CCS expression, protein carbonyl assays, survival assays in stationary-phase yeast The Journal of biological chemistry High 11500508
2004 The Cu-bound form of CCS (Cu-CCS) mediates oxidative formation of the conserved disulfide bond in SOD1 in vivo and in vitro, even in the presence of excess reductants. Cu-CCS facilitates cysteine oxidation and disulfide isomerization in a stepwise conversion of immature SOD1 to the active state. The disulfide status of SOD1 significantly affects the monomer-dimer equilibrium, CCS interaction, and enzyme activity. Biochemical activity assays with purified proteins in vitro and yeast in vivo, redox state analysis, monomer-dimer equilibrium measurement The EMBO journal High 15215895
2004 CCS mediates posttranslational activation of SOD1 in response to increases in oxygen tension; O2 (or superoxide) is required for SOD1 activation by CCS. Existing apo-pools of SOD1 are activated by CCS early in the oxidative response, prior to new SOD1 protein synthesis. Activity assays with pure proteins and cell extracts, translational blocking experiments, dose-response studies with O2 tension Proceedings of the National Academy of Sciences of the United States of America High 15064408
2004 In the absence of CCS, mammalian SOD1 can be activated through a secondary CCS-independent pathway involving glutathione (GSH). Yeast SOD1 cannot use this pathway due to dual prolines near the C-terminus; insertion of these prolines into human SOD1 renders it refractory to CCS-independent activation. Expression of human SOD1 in CCS-null yeast and mammalian cells, GSH depletion experiments, proline mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 15069187
2008 CCS over-expression in G93A SOD1 mice accelerates ALS disease and correlates with incomplete oxidation of the SOD1 intra-subunit disulfide in brain and spinal cord. A C244,246S CCS mutant that can interact with SOD1 but cannot insert copper or oxidize the disulfide still prevents SOD1 misfolding (detergent insolubility), indicating a copper-insertion-independent molecular chaperone function of CCS. Transgenic mouse model (G93A/CCS), redox state analysis of SOD1 disulfide in vivo, cell culture with CCS mutants, detergent solubility assays Human molecular genetics High 18337307
2008 Overexpression of CCS in G93A SOD1 mice causes an isolated cytochrome c oxidase (complex IV) deficiency in spinal cord, with 55% reduction in complex IV activity and marked reductions in COX1 and COX5b subunits, while activities of complexes I, II, III, and V are unaffected. Enzymatic activity assays of respiratory chain complexes, blue native PAGE, SDS-PAGE Western blotting, heme A analysis of spinal cord from CCS/G93A SOD1 transgenic mice The Journal of biological chemistry High 18334481
2009 CCS-dependent SOD1 activation requires molecular oxygen and results in disulfide oxidation dependent on both copper and O2, whereas the CCS-independent pathway can activate SOD1 under anaerobic conditions without forming the disulfide via CCS. Both pathways acquire copper from the same intracellular pool derived from cell-surface transporters. A proline at position 144 in yeast SOD1 is responsible for the strict copper/oxygen/CCS requirement for disulfide formation. Yeast expression system, anaerobic growth conditions, copper-depletion studies, mutagenesis of SOD1 proline residue, activity assays The Journal of biological chemistry High 19542232
2010 CCS mitochondrial distribution and IMS import is regulated by the Mia40/Erv1 disulfide relay system in a redox-dependent manner, and CCS in turn promotes SOD1 maturation and retention in the IMS through disulfide bond formation. Fractionation, genetic analyses in yeast and mammalian cells (review synthesis of mechanistic studies) Antioxidants & redox signaling Medium 20367259
2010 XIAP E3 ubiquitin ligase ubiquitinates CCS; this ubiquitination enhances CCS chaperone activity toward SOD1 rather than targeting CCS for proteasomal degradation. CCS mediates copper delivery to XIAP in cells. Co-immunoprecipitation, ubiquitination assays, SOD1 activity assays in cells with XIAP manipulation Molecular and cellular biology High 20154138
2012 A human CCS mutation (p.Arg163Trp) in domain II impairs CCS binding to SOD1, reduces CCS expression, and reduces SOD1 activity. This is the first human pathogenic mutation identified in a copper chaperone gene. CCS R163W fails to complement yeast Lys7Δ mutant. Immunoprecipitation, mammalian cell transfection, patient fibroblast biochemical analysis, yeast complementation assay Human mutation High 22508683
2015 The first domain of CCS (CCS1) is monomeric and can exchange copper with the cytosolic chaperone Atox1 in vitro; Cu transfer occurs in both directions and requires intact metal-binding cysteines. Full-length CCS also participates in this cross-pathway Cu exchange. NMR, size exclusion chromatography with 254/280 nm ratio as Cu loading indicator, Cys→Ala mutagenesis of Atox1 Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine Medium 25673218
2017 The SOD1-like domain of CCS (CCS-D2) forms a stable complex with zinc-bound SOD1 in human cells (shown by in-cell NMR), stabilizes mutant apo-SOD1 prior to zinc binding, prevents accumulation of unstructured mutant SOD1, and promotes zinc binding—demonstrating a molecular chaperone function distinct from copper insertion. In-cell NMR, in vitro NMR, cell-based stability assays for SOD1 mutants Scientific reports High 29234142
2017 SOD1 and CCS are S-acylated (palmitoylated) in human and mouse spinal cords. SOD1 and CCS form a highly stable heterodimer in human spinal cord that resists boiling, denaturants, and reducing agents; S-acylation is highest for SOD1-CCS heterodimers. CCS cysteine mutations that attenuate SOD1 maturation prevent heterodimer formation. Acyl resin-assisted capture (acyl-RAC) assay on human post-mortem and mouse spinal cord, HEK293 cell in vitro assays, cysteine mutagenesis Scientific reports High 28120938
2019 CCS stably interacts with the cytosolic C-terminal tail of the copper importer Ctr1 (Ctr1c) in a copper-dependent manner; this interaction becomes tripartite (Cu(I)-Ctr1c·CCS·SOD1 heterotrimer) upon addition of immature SOD1. Only complete SOD1 activation (copper delivery + disulfide bond formation) breaks the Ctr1c·CCS·SOD1 complex, indicating that activated SOD1 terminates the Ctr1-CCS interaction. Biochemical reconstitution in solution, pulldown/co-elution assays with purified proteins, engineered immature SOD1 forms Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine High 31292775
2020 Binding of SOD1 by CCS stabilizes a conformation of SOD1 that promotes site-specific high-affinity zinc binding. Several fALS-linked SOD1 mutations disrupt this CCS-promoted high-affinity zinc binding, suggesting that nonproductive Sod1 maturation by Ccs may be a common link across diverse fALS mutations. Zinc affinity measurements of wild-type and fALS SOD1 mutants in the presence or absence of CCS, biochemical binding assays Molecules (Basel, Switzerland) Medium 32121118
2021 CCS selectively binds to MEK1 and facilitates copper transfer to MEK1, promoting MEK1 kinase activity. CCS mutants that disrupt Cu(I) acquisition and exchange, or a CCS small-molecule inhibitor, reduce Cu-stimulated MEK1 kinase activity. Surface plasmon resonance, proximity-dependent biotin ligase (BioID) studies, CCS Cu-binding mutants, small-molecule CCS inhibitor, MEK1 kinase activity assays The Journal of biological chemistry High 34715128
2024 The pathogenic CCS variant R163W loses Zn binding at its SOD1-like domain (D2), gains unusually high-affinity Cu(I) binding in D2 with accompanying disulfide bond formation, and this diverts R163W CCS from copper chaperone to copper scavenger that accelerates SOD1 deactivation—acting as an 'anti-chaperone'. Comprehensive structural and biochemical analysis including Cu(II)→Cu(I) reduction assays, Zn binding measurements, disulfide detection, aggregation assays Biochemistry High 39099176
2024 The E3 ubiquitin ligase TRIM22 ubiquitinates CCS via K27-linked ubiquitination at Lys76 of CCS, targeting it for proteasomal degradation. TRIM22-mediated CCS degradation reduces ROS scavenging, increases reactive oxygen species, and inhibits STAT3 phosphorylation in breast cancer cells. The coiled-coil domain of TRIM22 is required for CCS ubiquitination. Label-free proteomics, Co-IP, ubiquitination assays, mutagenesis of TRIM22 coiled-coil domain and CCS Lys76, ROS assays, STAT3 phosphorylation assays Cancer letters High 39127340

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 A fraction of yeast Cu,Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria. A physiological role for SOD1 in guarding against mitochondrial oxidative damage. The Journal of biological chemistry 550 11500508
2004 Oxygen-induced maturation of SOD1: a key role for disulfide formation by the copper chaperone CCS. The EMBO journal 290 15215895
2021 CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction. The Canadian journal of cardiology 237 33827756
1998 The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase. The Journal of biological chemistry 217 9726962
1995 Oral captopril versus placebo among 13,634 patients with suspected acute myocardial infarction: interim report from the Chinese Cardiac Study (CCS-1). Lancet (London, England) 192 7885123
2004 Mechanisms for activating Cu- and Zn-containing superoxide dismutase in the absence of the CCS Cu chaperone. Proceedings of the National Academy of Sciences of the United States of America 143 15069187
2010 Import, maturation, and function of SOD1 and its copper chaperone CCS in the mitochondrial intermembrane space. Antioxidants & redox signaling 134 20367259
2004 Oxygen and the copper chaperone CCS regulate posttranslational activation of Cu,Zn superoxide dismutase. Proceedings of the National Academy of Sciences of the United States of America 109 15064408
1999 The copper chaperone CCS is abundant in neurons and astrocytes in human and rodent brain. Journal of neurochemistry 104 9886096
2020 CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation, SGLT2 Inhibitors, ARNI in HFpEF, and Tafamidis in Amyloidosis. The Canadian journal of cardiology 93 32036861
2005 Activation of CuZn superoxide dismutases from Caenorhabditis elegans does not require the copper chaperone CCS. The Journal of biological chemistry 75 16234242
2021 The copper chaperone CCS facilitates copper binding to MEK1/2 to promote kinase activation. The Journal of biological chemistry 73 34715128
2004 Cu,Zn-superoxide dismutase is lower and copper chaperone CCS is higher in erythrocytes of copper-deficient rats and mice. Experimental biology and medicine (Maywood, N.J.) 72 15337829
2003 Metallochaperone for Cu,Zn-superoxide dismutase (CCS) protein but not mRNA is higher in organs from copper-deficient mice and rats. Archives of biochemistry and biophysics 70 12941305
2018 Collision Cross Section (CCS) Database: An Additional Measure to Characterize Steroids. Analytical chemistry 69 29528626
1999 A gain of superoxide dismutase (SOD) activity obtained with CCS, the copper metallochaperone for SOD1. The Journal of biological chemistry 65 10601249
2010 Regulation of the copper chaperone CCS by XIAP-mediated ubiquitination. Molecular and cellular biology 64 20154138
2009 Activation of Cu,Zn-superoxide dismutase in the absence of oxygen and the copper chaperone CCS. The Journal of biological chemistry 62 19542232
2003 CCORT/CCS quality indicators for congestive heart failure care. The Canadian journal of cardiology 59 12704479
2008 Biological effects of CCS in the absence of SOD1 enzyme activation: implications for disease in a mouse model for ALS. Human molecular genetics 58 18337307
2013 A Benchmark Study on Error Assessment and Quality Control of CCS Reads Derived from the PacBio RS. Journal of data mining in genomics & proteomics 55 24179701
2016 Copper transporters and chaperones CTR1, CTR2, ATOX1, and CCS as determinants of cisplatin sensitivity. Metallomics : integrated biometal science 54 27157188
2018 Early Experience With CliniMACS Prodigy CCS (IFN-gamma) System in Selection of Virus-specific T Cells From Third-party Donors for Pediatric Patients With Severe Viral Infections After Hematopoietic Stem Cell Transplantation. Journal of immunotherapy (Hagerstown, Md. : 1997) 47 29239916
2020 Double crosslinked HLC-CCS hydrogel tissue engineering scaffold for skin wound healing. International journal of biological macromolecules 43 32240736
2003 CCORT/CCS quality indicators for acute myocardial infarction care. The Canadian journal of cardiology 43 12571693
2017 A molecular chaperone activity of CCS restores the maturation of SOD1 fALS mutants. Scientific reports 42 29234142
1984 Use of a newly established human cell line (SU-CCS-1) to demonstrate the relationship of clear cell sarcoma to malignant melanoma. Cancer research 41 6362860
2023 CRISPR/Cas9 screens unravel miR-3689a-3p regulating sorafenib resistance in hepatocellular carcinoma via suppressing CCS/SOD1-dependent mitochondrial oxidative stress. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 40 37924725
2019 Copper-zinc superoxide dismutase (Sod1) activation terminates interaction between its copper chaperone (Ccs) and the cytosolic metal-binding domain of the copper importer Ctr1. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 39 31292775
2018 Collision cross section (CCS) as a complementary parameter to characterize human and veterinary drugs. Analytica chimica acta 39 30392669
2008 Isolated cytochrome c oxidase deficiency in G93A SOD1 mice overexpressing CCS protein. The Journal of biological chemistry 36 18334481
2015 Human cytoplasmic copper chaperones Atox1 and CCS exchange copper ions in vitro. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 35 25673218
2011 A new intranasal influenza vaccine based on a novel polycationic lipid-ceramide carbamoyl-spermine (CCS). II. Studies in mice and ferrets and mechanism of adjuvanticity. Vaccine 34 21251901
2007 CCS and SOD1 mRNA are reduced after copper supplementation in peripheral mononuclear cells of individuals with high serum ceruloplasmin concentration. The Journal of nutritional biochemistry 33 17683925
2020 Mutations in Superoxide Dismutase 1 (Sod1) Linked to Familial Amyotrophic Lateral Sclerosis Can Disrupt High-Affinity Zinc-Binding Promoted by the Copper Chaperone for Sod1 (Ccs). Molecules (Basel, Switzerland) 31 32121118
2020 Circ-CCS is identified as a cancer-promoting circRNA in lung cancer partly by regulating the miR-383/E2F7 axis. Life sciences 31 33359669
2016 Roles of calpain-calpastatin system (CCS) in human T cell activation. Oncotarget 28 27835610
2013 Species-specific activation of Cu/Zn SOD by its CCS copper chaperone in the pathogenic yeast Candida albicans. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 28 24043471
2012 Molecular and biochemical characterization of a unique mutation in CCS, the human copper chaperone to superoxide dismutase. Human mutation 26 22508683
2009 Redox susceptibility of SOD1 mutants is associated with the differential response to CCS over-expression in vivo. Neurobiology of disease 26 19320055
2006 A novel cervical cancer suppressor 3 (CCS-3) interacts with the BTB domain of PLZF and inhibits the cell growth by inducing apoptosis. FEBS letters 23 16828757
1986 Optimized conditions for solid-phase sequencing: simultaneous chemical cleavage of a series of long DNA fragments immobilized on CCS anion-exchange paper. Gene 23 3721198
2014 Establishment of a novel clear cell sarcoma cell line (Hewga-CCS), and investigation of the antitumor effects of pazopanib on Hewga-CCS. BMC cancer 22 24946937
2024 The E3 ligase TRIM22 functions as a tumor suppressor in breast cancer by targeting CCS for proteasomal degradation to inhibit STAT3 signaling. Cancer letters 19 39127340
2017 S-acylation of SOD1, CCS, and a stable SOD1-CCS heterodimer in human spinal cords from ALS and non-ALS subjects. Scientific reports 16 28120938
2013 Targeted therapies in rare sarcomas: IMT, ASPS, SFT, PEComa, and CCS. Hematology/oncology clinics of North America 16 24093175
1999 A model for the incorporation of metal from the copper chaperone CCS into Cu,Zn superoxide dismutase. Structure (London, England : 1993) 16 10467139
2009 Eukaryotic translation initiator protein 1A isoform, CCS-3, enhances the transcriptional repression of p21CIP1 by proto-oncogene FBI-1 (Pokemon/ZBTB7A). Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 15 19471103
2015 Hazard assessment of nitrosamine and nitramine by-products of amine-based CCS: alternative approaches. Regulatory toxicology and pharmacology : RTP 14 25604881
2013 Expression of calpain-calpastatin system (CCS) member proteins in human lymphocytes of young and elderly individuals; pilot baseline data for the CALPACENT project. Immunity & ageing : I & A 14 23835405
2010 The cardiac copper chaperone proteins Sco1 and CCS are up-regulated, but Cox 1 and Cox4 are down-regulated, by copper deficiency. Biological trace element research 14 20878365
2005 Transduced human copper chaperone for Cu,Zn-SOD (PEP-1-CCS) protects against neuronal cell death. Molecules and cells 14 16404156
2011 Boron neutron capture therapy for clear cell sarcoma (CCS): biodistribution study of p-borono-L-phenylalanine in CCS-bearing animal models. Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine 13 21367607
2024 CIUSuite 3: Next-Generation CCS Calibration and Automated Data Analysis Tools for Gas-Phase Protein Unfolding Data. Journal of the American Society for Mass Spectrometry 12 38967378
2015 Boron neutron capture therapy (BNCT) as a new approach for clear cell sarcoma (CCS) treatment: Trial using a lung metastasis model of CCS. Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine 12 26337135
2024 BDNF- and VEGF-Responsive Stimulus to an NGF Mimic Cyclic Peptide with Copper Ionophore Capability and Ctr1/CCS-Driven Signaling. ACS chemical neuroscience 11 38602894
2022 Circ-CCS enhances autophagy during imatinib resistance of gastrointestinal stromal tumor by regulating miR-197-3p/ATG10 signaling. Journal of cancer research and therapeutics 11 36204881
2020 Intravenous anti-VEGF agents with RGD peptide-targeted core cross-linked star (CCS) polymers modified with indocyanine green for imaging and treatment of laser-induced choroidal neovascularization. Biomaterials science 11 32609105
2011 Evaluation of BPA uptake in clear cell sarcoma (CCS) in vitro and development of an in vivo model of CCS for BNCT studies. Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine 11 21354804
2011 Opposite temperature effect on transport activity of KCC2/KCC4 and N(K)CCs in HEK-293 cells. BMC research notes 11 22152068
2007 Complex genomic rearrangement in CCS-LacZ transgenic mice. Genesis (New York, N.Y. : 2000) 11 17269130
2022 Molecular Hallmarks of Ischemia with Non-Obstructive Coronary Arteries: The "INOCA versus Obstructive CCS" Challenge. Journal of clinical medicine 10 35330036
2022 Association of MMP9 with adverse features of plaque progression and residual inflammatory risk in patients with chronic coronary syndrome (CCS). Vascular pharmacology 10 36100166
2014 Regulation of the chloroplastic copper chaperone (CCS) and cuprozinc superoxide dismutase (CSD2) by alternative splicing and copper excess in Glycine max. Functional plant biology : FPB 10 32480974
2010 Decreased erythrocyte CCS content is a biomarker of copper overload in rats. International journal of molecular sciences 10 20717526
1997 Oral captopril versus placebo among 14,962 patients with suspected acute myocardial infarction: a multicenter, randomized, double-blind, placebo controlled clinical trial. Chinese Cardiac Study (CCS-1) Collaborative Group. Chinese medical journal 10 9772413
2023 Genome-Wide Identification and Characterization of Copper Chaperone for Superoxide Dismutase (CCS) Gene Family in Response to Abiotic Stress in Soybean. International journal of molecular sciences 9 36982229
2011 Effect of CCS on the accumulation of FALS SOD1 mutant-containing aggregates and on mitochondrial translocation of SOD1 mutants: implication of a free radical hypothesis. Archives of biochemistry and biophysics 9 21354101
2002 Human CCS gene: genomic organization and exclusion as a candidate for amyotrophic lateral sclerosis (ALS). BMC genetics 9 11991808
2016 CO2 leakage from carbon dioxide capture and storage (CCS) systems affects organic matter cycling in surface marine sediments. Marine environmental research 8 27816195
2022 H3K27 acetylation activated-CCS regulates autophagy and apoptosis of lung cancer by alleviating oxidative stress. Tissue & cell 7 36402120
2017 Analysis of tandem repeat units of the promoter of capsanthin/capsorubin synthase (Ccs) gene in pepper fruit. Physiology and molecular biology of plants : an international journal of functional plant biology 7 28878506
2025 Clear Cell Sarcoma (CCS) of the Soft Tissue: An Update Narrative Review with Emphasis on the Utility of PRAME in Differential Diagnosis. Journal of clinical medicine 6 40004764
2025 SMAC: identifying DNA N6-methyladenine (6mA) at the single-molecule level using SMRT CCS data. Briefings in bioinformatics 6 40205850
2022 Circ-CCS regulates oxaliplatin resistance via targeting miR-874-3p/HK2 axis in colorectal cancer. Histology and histopathology 6 36519522
2014 Genetics of rare mesenchymal tumors: implications for targeted treatment in DFSP, ASPS, CCS, GCTB and PEComa. The international journal of biochemistry & cell biology 6 24704529
2024 Medicinal cannabis oil improves anxiety-like and depressive-like behaviors in CCS mice via the BDNF/TRPC6 signaling pathway. Behavioural brain research 5 38641178
2023 Waste-to-energy and waste-to-hydrogen with CCS: Methodological assessment of pathways to carbon-negative waste treatment from an LCA perspective. Waste management (New York, N.Y.) 5 38000195
2011 Characterization of the recombinant copper chaperone (CCS) from the plant Glycine (G.) max. Metallomics : integrated biometal science 5 21264427
2024 The Impact of CYP2C19 Genotype on the Platelet Reactivity Index (PRI) among Chronic Coronary Syndromes (CCS) Patients Undergoing Percutaneous Coronary Intervention (PCI): Affectability of Rapid Genetic Testing. Cardiovascular drugs and therapy 3 38224415
2024 Pathogenic R163W Variant of the Copper Chaperone for Sod1 (Ccs) Functions as an Anti-chaperone. Biochemistry 3 39099176
2020 The cationic liposome CCS/C adjuvant induces immunity to influenza independently of the adaptor protein MyD88. Human vaccines & immunotherapeutics 3 32401698
2014 CCS mRNA transcripts and serum CCS protein as copper marker in adults suffering inflammatory processes. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 3 24855044
2024 Enzyme-accelerated CO2 capture and storage (CCS) using paper and pulp residues as co-sequestrating agents. RSC advances 2 38380236
2023 A Comparative Study of CCM and CCS Membrane Electrode Assemblies for High-Temperature Proton Exchange Membrane Fuel Cells with a CsH5(PO4)2-Doped Polybenzimidazole Membrane. Materials (Basel, Switzerland) 2 37297059
2025 CCS-Consensuser: A Haplotype-Aware Consensus Generator for PacBio Amplicon Sequences. Molecular ecology resources 1 40181733
2025 Conference on challenges in sarcoma (CCS) 2024: Expert opinions on non-evidence-based management aspects. European journal of cancer (Oxford, England : 1990) 1 40184845
2024 Short-term and Long-term Stability of the Autism Diagnostic Observation Schedule (ADOS-2) Calibrated Comparison Scores (CCS) and Classification Scores in Youth with Down Syndrome or Fragile X Syndrome with Intellectual Disability. Journal of autism and developmental disorders 1 39251531
2023 Fabrication of ACP-CCS-PVA composite membrane for a potential application in guided bone regeneration. RSC advances 1 37664206
2011 [Design and biological evaluation of poly-lactic-co-glycolic acid (PLGA) mesh/collagen-chitosan hybrid scaffold (CCS) as a dermal substitute]. Zhonghua shao shang za zhi = Zhonghua shaoshang zazhi = Chinese journal of burns 1 21591335
2026 Comprehensive IM-MS approach for SARMs detection in urine: building CCS databases to support food safety monitoring. Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment 0 41747154
2026 CCS-mediated mechanistic link between gestational diabetes mellitus and carpal tunnel syndrome: a multi-omics MR framework. Frontiers in immunology 0 41890708
2026 CCS facilitates the progression of ovarian cancer by suppressing ferroptotic cell death via the modulation of p53-mediated expression of SLC7A11 and GPX4. Acta pharmacologica Sinica 0 42144443
2025 Generalization of the CCS-Mass Equation to Account for Variations in Molecular Density in an Iron-Ligand Complex Growing System. Rapid communications in mass spectrometry : RCM 0 40211889
2025 NanoBiT-based Analysis of Canine SOD1 Protein Dynamics: Understanding the Role of CCS and Ebselen Derivatives as Potential Therapeutics for Canine Degenerative Myelopathy. Cell biochemistry and biophysics 0 40355776
2025 Differential effects of dual antiplatelet and dual antithrombotic therapy on hemostasis in chronic coronary syndrome patients: the DEFINE CCS study. Platelets 0 40605742
2025 Efficacy and Safety of Low-Dose Rivaroxaban in High-Ischemic-Risk Patients with Chronic Coronary Syndrome: Rationale and Design of the DUTCH CCS Registry. Journal of clinical medicine 0 40648772
2025 The Role of Targeted Therapy and Immunotherapy in Metastatic GNET/Clear Cell Sarcoma (CCS) of the Gastrointestinal Tract: A Case Report. Current issues in molecular biology 0 41020828
2025 Systemic Risks of Excessive CCS Deployment in Power-Sector Decarbonization. Environmental science & technology 0 41454861
1987 Solid-phase methods for sequencing nucleic acids. VII. Chemical degradation of synthetic DNA-RNA hybrid fragments using CCS and DE 81 anion-exchange papers. Nucleic acids symposium series 0 2447566

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