Affinage

CCS

Copper chaperone for superoxide dismutase · UniProt O14618

Length
274 aa
Mass
29.0 kDa
Annotated
2026-04-28
100 papers in source corpus 22 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCS is a multi-domain copper metallochaperone that acquires Cu(I) from the cytoplasmic tail of the copper importer Ctr1 and delivers it to SOD1 through formation of a transient heterodimeric complex mediated by its SOD1-homologous domain (domain II), simultaneously catalyzing oxygen-dependent intra-subunit disulfide bond formation and promoting zinc loading to generate mature, active SOD1 (PMID:9726962, PMID:15215895, PMID:31292775, PMID:29234142). Beyond SOD1 maturation, CCS delivers copper to MEK1 to stimulate RAF-MEK-ERK signaling (PMID:34715128), and a fraction of CCS is imported into the mitochondrial intermembrane space via the Mia40/Erv1 disulfide relay to drive SOD1 activation in mitochondria, where it protects against oxidative damage (PMID:11500508, PMID:20367259). CCS activity is post-translationally regulated by XIAP-mediated ubiquitination that enhances chaperone function and by TRIM22-mediated K27-linked ubiquitination at Lys76 that directs proteasomal degradation (PMID:20154138, PMID:39127340). The pathogenic human CCS R163W mutation disrupts zinc binding in domain II, converts CCS from a copper chaperone into a copper-scavenging anti-chaperone that deactivates SOD1, and represents the first described disease-causing mutation in a copper chaperone gene (PMID:22508683, PMID:39099176).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 High

    Establishing CCS as a direct physical partner of SOD1 answered the fundamental question of how copper reaches SOD1, revealing a dedicated chaperone–target interaction mediated by the SOD1-homologous domain II of CCS.

    Evidence Reciprocal co-immunoprecipitation and in vitro pulldown with domain mapping using wild-type and FALS mutant SOD1

    PMID:9726962

    Open questions at the time
    • Structure of the CCS–SOD1 heterodimer was not determined
    • Copper transfer step was not directly visualized
    • Stoichiometry and affinity of the complex not quantified
  2. 1999 High

    Structural dissection of CCS domain II showed it conserves zinc-binding ligands but evolved Asp200 in place of the fourth copper-binding histidine to prevent superoxide dismutase side-reactions, explaining how a SOD1-like scaffold was repurposed for chaperone function.

    Evidence Site-directed mutagenesis with D200H gain-of-SOD-activity assay in yeast; CCS localization to ALS-vulnerable neurons by immunohistochemistry

    PMID:10601249 PMID:9886096

    Open questions at the time
    • How CCS itself acquires copper from upstream sources was not addressed
    • Relevance of the 12–30× molar excess of SOD1 over CCS for activation kinetics unclear
  3. 2001 High

    Discovery that CCS drives SOD1 accumulation in the mitochondrial intermembrane space—despite neither protein having a canonical presequence—revealed an unexpected compartmentalized function for the chaperone in organellar antioxidant defense.

    Evidence Subcellular fractionation, overexpression, protein carbonyl assays, and survival assays in S. cerevisiae

    PMID:11500508

    Open questions at the time
    • The import mechanism (later linked to Mia40/Erv1) was not yet defined
    • Whether mitochondrial CCS-SOD1 pathway operates identically in mammalian cells was untested
  4. 2004 High

    Reconstitution of CCS-catalyzed disulfide bond formation in SOD1 established that CCS is not merely a copper donor but an oxidoreductase that couples copper insertion with oxygen-dependent disulfide isomerization, defining the full activation mechanism. Parallel work showed a CCS-independent, glutathione-dependent activation pathway exists for mammalian but not yeast SOD1.

    Evidence In vitro reconstitution with purified proteins, in vivo yeast assays, translational blocking, anaerobic experiments, proline-insertion mutagenesis, fibroblast activity assays

    PMID:15064408 PMID:15069187 PMID:15215895

    Open questions at the time
    • Structural basis of the CCS active-site redox chemistry was unresolved
    • Relative flux through CCS-dependent vs. CCS-independent pathways in human tissues unknown
  5. 2008 High

    Transgenic mouse studies showed that CCS overexpression paradoxically accelerates SOD1-linked ALS disease, associated with incomplete SOD1 disulfide oxidation and isolated cytochrome c oxidase deficiency—demonstrating that CCS has copper-independent biological effects and that dysregulated CCS–SOD1 stoichiometry can be pathogenic.

    Evidence G93A SOD1 transgenic mice crossed with CCS-overexpressing mice; C244,246S CCS mutant retaining SOD1 binding but lacking copper/disulfide activity; respiratory chain complex assays in spinal cord

    PMID:18334481 PMID:18337307

    Open questions at the time
    • Mechanism linking CCS overexpression to complex IV deficiency was not established
    • Whether CCS-independent chaperone activity is protective or toxic in physiological settings remained ambiguous
  6. 2010 High

    Identification of XIAP as an E3 ligase that ubiquitinates CCS to enhance (not degrade) its chaperone activity, coupled with evidence that CCS delivers copper to XIAP, revealed a regulatory feedback loop linking copper metabolism to apoptosis signaling. Concurrent work established the Mia40/Erv1 disulfide relay as the mitochondrial import mechanism for CCS.

    Evidence Co-IP, ubiquitination assays, SOD1 activity readouts; integrative analysis of IMS import/retention data

    PMID:20154138 PMID:20367259

    Open questions at the time
    • Sites of XIAP-mediated ubiquitination on CCS not mapped
    • Whether XIAP ubiquitination regulates the mitochondrial pool of CCS unknown
  7. 2012 High

    Discovery of the CCS R163W mutation in a human patient—the first pathogenic mutation in a copper chaperone—linked impaired CCS–SOD1 interaction and reduced SOD1 activity to human disease, validating the physiological essentiality of CCS.

    Evidence Patient fibroblast analysis, co-immunoprecipitation, yeast complementation

    PMID:22508683

    Open questions at the time
    • Structural basis for R163W dysfunction not yet determined
    • Clinical spectrum and prevalence of CCS mutations unknown
  8. 2017 High

    In-cell NMR demonstrated that CCS domain II forms a stable zinc-loaded complex with SOD1 inside living cells and acts as a molecular chaperone by stabilizing apo-SOD1 and promoting zinc binding, independent of copper transfer. Parallel work identified S-acylation (palmitoylation) of both CCS and SOD1 in human spinal cord, with highest modification in the heterodimeric maturation intermediate.

    Evidence In-cell and in vitro NMR with CCS-D2 domain construct; acyl-RAC assay with cysteine mutation controls in human post-mortem spinal cord and mouse tissue

    PMID:28120938 PMID:29234142

    Open questions at the time
    • Functional consequence of S-acylation for CCS activity or SOD1 maturation not tested
    • Identity of the palmitoyl acyltransferase(s) targeting CCS unknown
  9. 2019 High

    Reconstitution of a Cu(I)-Ctr1c·CCS·SOD1 heterotrimer showed that CCS acquires copper directly from the Ctr1 cytoplasmic tail and that only complete SOD1 activation (copper delivery plus disulfide formation) terminates this complex, establishing a product-release feedback mechanism governing upstream copper acquisition.

    Evidence In vitro reconstitution with purified Ctr1c, CCS, and engineered immature SOD1; size exclusion chromatography; copper-dependent interaction assays

    PMID:31292775

    Open questions at the time
    • Whether the tripartite complex forms at endogenous protein concentrations in cells not shown
    • Regulation of Ctr1c–CCS interaction by other post-translational modifications untested
  10. 2021 High

    Identification of CCS as a direct copper-delivery factor for MEK1 kinase expanded the functional repertoire of CCS beyond SOD1, placing it in the RAF-MEK-ERK signaling pathway and revealing a broader role in copper-dependent cell signaling.

    Evidence Surface plasmon resonance for direct binding, BioID proximity labeling, CCS Cu-binding mutants, small-molecule CCS inhibitor, MEK1 kinase activity assays

    PMID:34715128

    Open questions at the time
    • Whether CCS delivers copper to other kinases or signaling proteins is unknown
    • In vivo relevance of CCS–MEK1 axis in animal models not tested
  11. 2024 High

    Mechanistic dissection of the R163W pathogenic mutation revealed it abolishes zinc binding in domain II, causing aberrant high-affinity Cu(I) acquisition and converting CCS into an anti-chaperone that deactivates SOD1—explaining the molecular basis of disease. Separately, TRIM22 was identified as a second E3 ligase for CCS, mediating K27-linked ubiquitination at Lys76 for proteasomal degradation with functional consequences for ROS and STAT3 signaling.

    Evidence Structural/functional characterization of purified R163W protein with Cu(I) binding, redox, and aggregation assays; label-free proteomics, ubiquitination site mapping, domain deletion mutants for TRIM22

    PMID:39099176 PMID:39127340

    Open questions at the time
    • No structural model of the R163W CCS–SOD1 aberrant complex exists
    • Relative contributions of XIAP vs. TRIM22 ubiquitination to CCS homeostasis in different tissues unknown
    • TRIM22–CCS axis validated only in breast cancer cell lines

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full structural basis of the CCS–SOD1 copper-transfer/disulfide-relay mechanism at atomic resolution, the physiological significance of CCS palmitoylation, the complete inventory of CCS copper clients beyond SOD1 and MEK1, and the tissue-specific integration of XIAP and TRIM22 ubiquitination pathways in regulating CCS levels.
  • No high-resolution structure of the human CCS–SOD1 transient complex during copper transfer
  • Functional role of S-acylation in CCS-mediated SOD1 maturation untested
  • Full client repertoire of CCS as a copper chaperone undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140104 molecular carrier activity 5 GO:0044183 protein folding chaperone 3 GO:0098772 molecular function regulator activity 3 GO:0016491 oxidoreductase activity 2
Localization
GO:0005829 cytosol 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-382551 Transport of small molecules 4 R-HSA-392499 Metabolism of proteins 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-162582 Signal Transduction 1
Partners
ATOX1CTR1MEK1MIA40SOD1TRIM22XIAP
Complex memberships
Cu(I)-Ctr1c·CCS·SOD1 heterotrimerSOD1-CCS heterodimer

Evidence

Reading pass · 22 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 SOD1-homologous domain (domain II) of CCS. CCS interacts with both wild-type and FALS mutant SOD1. Co-immunoprecipitation, in vitro pulldown, domain mapping The Journal of biological chemistry High 9726962
1999 CCS contains a central domain with ~50% identity to SOD1, conserving all zinc-binding ligands and three of four copper-binding histidines (the fourth is Asp200). A single D200H mutation confers superoxide dismutase activity to CCS without abolishing its copper chaperone function, demonstrating that Asp200 evolved to prevent deleterious copper reactions in CCS. Site-directed mutagenesis, SOD activity assay in yeast expression system The Journal of biological chemistry High 10601249
1999 CCS localizes to neurons and astrocytes in human and rodent brain, colocalizing with SOD1 in the same cell types that degenerate in ALS, including motor neurons, Purkinje cells, and pyramidal cortical neurons. SOD1 is present at 12–30-fold molar excess over CCS. Immunohistochemistry with monospecific antibodies in human and mouse brain/spinal cord Journal of neurochemistry Medium 9886096
2001 A fraction of CCS and active SOD1 localize to the mitochondrial intermembrane space (IMS) in yeast. CCS drives mitochondrial accumulation of SOD1 (neither protein contains a canonical mitochondrial presequence). Enrichment of IMS SOD1 via CCS overexpression protects against oxidative damage and prolongs survival in stationary phase. Subcellular fractionation, repressible promoter experiments, protein carbonyl assays, survival assays in S. cerevisiae The Journal of biological chemistry High 11500508
2004 Cu-bound CCS (Cu-CCS) catalyzes oxidation of the conserved disulfide bond in SOD1 and facilitates disulfide isomerization in a stepwise conversion from immature to active SOD1, both in vivo and in vitro, even in the presence of excess reductants. Disulfide formation by CCS requires oxygen. Biochemical in vitro reconstitution assays, in vivo activity assays in S. cerevisiae, disulfide status analysis The EMBO journal High 15215895
2004 CCS mediates oxygen-responsive posttranslational activation of SOD1: O2 (or superoxide) is required for CCS-dependent SOD1 activation. Apo-pools of SOD1 are activated rapidly by CCS upon increased oxygen tension before new SOD1 protein is synthesized. Activity assays with purified proteins and cell extracts, translational blocking agent (dose-response), O2 tension variation Proceedings of the National Academy of Sciences of the United States of America High 15064408
2004 CCS-independent activation of mammalian SOD1 (but not yeast SOD1) requires glutathione (GSH). Dual prolines near the C-terminus of yeast SOD1 render it refractory to CCS-independent activation; inserting these prolines into human SOD1 blocks the CCS-independent pathway. Genetic complementation in yeast null for CCS, glutathione depletion, proline insertion mutagenesis, activity assays in immortalized fibroblasts Proceedings of the National Academy of Sciences of the United States of America High 15069187
2008 CCS over-expression in G93A SOD1 ALS mice accelerates disease and is associated with incomplete oxidation of the SOD1 disulfide (accumulation of disulfide-reduced SOD1 in brain and spinal cord). A C244,246S CCS mutant that cannot insert copper or oxidize the disulfide still interacts with SOD1, prevents SOD1 misfolding/aggregation, and accelerates disease, indicating CCS has copper-chaperone-independent biological effects. Transgenic mouse model, immunoblot for SOD1 disulfide status, detergent-insolubility assay, cell culture with CCS mutants Human molecular genetics High 18337307
2008 CCS over-expression in G93A SOD1 mice produces an isolated cytochrome c oxidase (complex IV) deficiency in spinal cord (55% loss of activity), with selective reduction of COX1 and COX5b subunits and reduced heme A, but no deficit in complexes I, II, III, or V. Enzyme activity assays of mitochondrial respiratory chain complexes, blue native PAGE, SDS-PAGE Western blot, heme A analysis in transgenic mouse spinal cord The Journal of biological chemistry High 18334481
2009 CCS-dependent SOD1 activation strictly requires copper, oxygen, and CCS for disulfide bond oxidation; a unique proline at position 144 of yeast SOD1 is responsible for this strict oxygen requirement. CCS-independent activation (in metazoan SOD1s) can occur anaerobically and without CCS. Both pathways acquire copper from the same intracellular pool derived from cell-surface transporters. Yeast expression system, anaerobic growth assays, mutagenesis at Pro144, copper competition experiments The Journal of biological chemistry High 19542232
2010 CCS import into the mitochondrial IMS is regulated by the Mia40/Erv1 disulfide relay system in a redox-dependent manner. CCS in turn promotes SOD1 maturation and retention in the IMS through disulfide bond formation. Review integrating genetic and biochemical data on IMS import/retention mechanisms (fractionation, redox studies) Antioxidants & redox signaling Medium 20367259
2010 XIAP ubiquitinates CCS via its E3 ubiquitin ligase activity. Ubiquitination of CCS by XIAP enhances CCS chaperone activity toward SOD1 rather than directing CCS to proteasomal degradation. CCS mediates copper delivery to XIAP in cells. Co-immunoprecipitation, ubiquitination assays, mass spectrometry identification, SOD1 activity assays in cells Molecular and cellular biology High 20154138
2011 CCS acts as a molecular chaperone independent of copper insertion: CCS can facilitate degradation of inactive G85R SOD1 via macroautophagy, reduce aggregation of inactive mutants, and promote maturation of active G93A and A4V SOD1. CCS is itself degraded primarily via a macroautophagy pathway. Under oxidative conditions (H2O2), CCS facilitates mitochondrial translocation of inactive SOD1 mutants. Dicistronic AAV293 cell expression system, autophagy inhibitor studies, immunoprecipitation, subcellular fractionation, Western blot Archives of biochemistry and biophysics Medium 21354101
2012 The human CCS R163W mutation (in the SOD1-like domain II, adjacent to a conserved Zn-binding site) reduces CCS expression, impairs CCS binding to SOD1, and reduces SOD1 activity. This is the first described pathogenic human mutation in a copper chaperone gene. Patient fibroblast biochemical analysis, mammalian cell transfection, co-immunoprecipitation, yeast complementation assays Human mutation High 22508683
2015 Human CCS domain 1 (CCS1) and full-length CCS can exchange copper with the copper chaperone Atox1 in vitro; this exchange requires the metal-binding cysteine of Atox1. CCS1 is monomeric in solution. NMR, size exclusion chromatography with 254/280 nm ratio as Cu-loading indicator, Cu transfer assays with Atox1 cysteine mutant Biometals Medium 25673218
2017 The SOD1-like domain of CCS (CCS-D2) forms a stable complex with zinc-bound SOD1 inside human cells (demonstrated by in-cell NMR), stabilizes mutant apo-SOD1 before zinc binding, prevents accumulation of unstructured mutant SOD1, and promotes zinc binding, acting as a molecular chaperone independent of copper transfer. In-cell NMR, in vitro NMR, cell transfection with CCS-D2 domain construct Scientific reports High 29234142
2017 CCS and SOD1 form a highly stable, S-acylated (palmitoylated) heterodimer in human spinal cord that resists dissociation by boiling, denaturants, or reducing agents. Both endogenous CCS and SOD1 are S-acylated in human and mouse spinal cord. S-acylation is highest in the SOD1-CCS heterodimer intermediate, suggesting membrane anchoring plays a role in CCS-mediated SOD1 maturation. Acyl resin-assisted capture (acyl-RAC) assay, cysteine mutation analysis, human post-mortem spinal cord and mouse tissue, HEK293 cells Scientific reports Medium 28120938
2019 CCS stably interacts with the cytosolic C-terminal tail of the copper importer Ctr1 (Ctr1c) in a copper-dependent manner, forming a Cu(I)-Ctr1c·CCS·SOD1 heterotrimer with immature SOD1. Only complete SOD1 activation (copper delivery plus disulfide bond formation) terminates the Ctr1c-CCS-SOD1 complex, revealing that SOD1 activation status regulates upstream copper acquisition by CCS. In vitro biochemical reconstitution, size exclusion chromatography, copper-dependent interaction assays with engineered immature SOD1 Biometals High 31292775
2020 CCS binding to SOD1 stabilizes a SOD1 conformation that promotes site-specific high-affinity zinc binding; fALS-linked SOD1 mutations disrupt this CCS-promoted zinc binding, suggesting that impaired zinc loading is a common mechanistic feature of diverse fALS mutants. Zinc affinity measurements, biochemical binding assays with CCS and fALS mutant SOD1 panel Molecules Medium 32121118
2021 CCS selectively binds MEK1 via direct protein-protein interaction and facilitates copper transfer to MEK1, stimulating MEK1 kinase activity. CCS mutants that disrupt Cu(I) acquisition/exchange or a CCS small-molecule inhibitor reduce Cu-stimulated MEK1 kinase activity, placing CCS in the RAF-MEK-ERK signaling pathway as a copper delivery factor. Surface plasmon resonance, proximity-dependent biotin ligase (BioID), CCS Cu-binding mutants, small-molecule CCS inhibitor, MEK1 kinase activity assays The Journal of biological chemistry High 34715128
2024 The pathogenic CCS R163W mutation causes loss of Zn binding in domain 2 (D2), generates an unstable Zn-deficient protein that acquires aberrant high-affinity Cu(I) in D2, and converts CCS from a copper chaperone to a copper scavenger (anti-chaperone) that accelerates SOD1 deactivation. Disulfide bond formation in D2 accompanies aberrant Cu(I) binding and promotes aggregation. Structural and functional analysis with purified R163W protein, Cu(I) binding assays, redox assays, SOD1 activation assays, aggregation studies Biochemistry High 39099176
2024 TRIM22 ubiquitinates CCS via K27-linked ubiquitin chains at lysine 76 of CCS, targeting CCS for proteasomal degradation. TRIM22's coiled-coil domain is required for CCS ubiquitination. CCS ubiquitination/degradation reduces ROS levels and inhibits STAT3 phosphorylation in breast cancer cells. Label-free proteomics, co-immunoprecipitation, ubiquitination assays, domain deletion mutants, ectopic CCS rescue experiments, ChIP-qPCR Cancer letters Medium 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 548 11500508
2004 Oxygen-induced maturation of SOD1: a key role for disulfide formation by the copper chaperone CCS. The EMBO journal 287 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 226 33827756
1998 The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase. The Journal of biological chemistry 215 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 131 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
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.) 71 15337829
2021 The copper chaperone CCS facilitates copper binding to MEK1/2 to promote kinase activation. The Journal of biological chemistry 70 34715128
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 69 12941305
2018 Collision Cross Section (CCS) Database: An Additional Measure to Characterize Steroids. Analytical chemistry 68 29528626
2010 Regulation of the copper chaperone CCS by XIAP-mediated ubiquitination. Molecular and cellular biology 64 20154138
1999 A gain of superoxide dismutase (SOD) activity obtained with CCS, the copper metallochaperone for SOD1. The Journal of biological chemistry 64 10601249
2009 Activation of Cu,Zn-superoxide dismutase in the absence of oxygen and the copper chaperone CCS. The Journal of biological chemistry 60 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 57 18337307
2016 Copper transporters and chaperones CTR1, CTR2, ATOX1, and CCS as determinants of cisplatin sensitivity. Metallomics : integrated biometal science 54 27157188
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 54 24179701
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) 46 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 41 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
2015 Chloroplast genome of Aconitum barbatum var. puberulum (Ranunculaceae) derived from CCS reads using the PacBio RS platform. Frontiers in plant science 39 25705213
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 38 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 37 31292775
2018 Collision cross section (CCS) as a complementary parameter to characterize human and veterinary drugs. Analytica chimica acta 37 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 34 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) 30 32121118
2020 Circ-CCS is identified as a cancer-promoting circRNA in lung cancer partly by regulating the miR-383/E2F7 axis. Life sciences 30 33359669
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
2016 Roles of calpain-calpastatin system (CCS) in human T cell activation. Oncotarget 27 27835610
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 21 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 16 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
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 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 11 38967378
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
2024 BDNF- and VEGF-Responsive Stimulus to an NGF Mimic Cyclic Peptide with Copper Ionophore Capability and Ctr1/CCS-Driven Signaling. ACS chemical neuroscience 10 38602894
2022 Molecular Hallmarks of Ischemia with Non-Obstructive Coronary Arteries: The "INOCA versus Obstructive CCS" Challenge. Journal of clinical medicine 10 35330036
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 10 36204881
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
2022 Association of MMP9 with adverse features of plaque progression and residual inflammatory risk in patients with chronic coronary syndrome (CCS). Vascular pharmacology 9 36100166
2012 Models for the mechanism for activating copper-zinc superoxide dismutase in the absence of the CCS Cu chaperone in Arabidopsis. Plant signaling & behavior 9 22476460
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 6 36402120
2022 Circ-CCS regulates oxaliplatin resistance via targeting miR-874-3p/HK2 axis in colorectal cancer. Histology and histopathology 6 36519522
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 6 28878506
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
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 5 40004764
2025 SMAC: identifying DNA N6-methyladenine (6mA) at the single-molecule level using SMRT CCS data. Briefings in bioinformatics 5 40205850
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
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 Pathogenic R163W Variant of the Copper Chaperone for Sod1 (Ccs) Functions as an Anti-chaperone. Biochemistry 1 39099176
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 CCS-mediated mechanistic link between gestational diabetes mellitus and carpal tunnel syndrome: a multi-omics MR framework. Frontiers in immunology 0 41890708
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 Photolytic Release of CS2 from Bis(Tritylthiocarbonyl) Disulfide, Ph3CC(S)SS(S)CCPh3. Inorganic chemistry 0 40904021
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