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Gene Review

CCS  -  copper chaperone for superoxide dismutase

Homo sapiens

Synonyms: Copper chaperone for superoxide dismutase, Superoxide dismutase copper chaperone
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Disease relevance of CCS

  • Elucidation of the CCS copper delivery pathway may permit development of novel therapeutic approaches to human diseases that involve SOD1, including amyotrophic lateral sclerosis [1].
  • In the present study, we investigated the chronological alterations in SOD1 and its copper chaperone (chaperone for superoxide dismutase, CCS) immunoreactivities and their neuroprotective effects against neuronal damage in the gerbil hippocampus after 5 min of transient forebrain ischemia [2].
  • Since a copper-mediated toxicity hypothesis has been proposed to explain the cytotoxic gain-of-function of mutant SOD1, we sought to determine the involvement of the copper chaperone for SOD1 (CCS) in the formation of protein aggregates [3].
  • Our data also confirmed that copper transporters and chaperones are involved in OXA resistance in colorectal cancer cells as evidenced by the overexpression of ATP7A and CCS in response to OXA exposure [4].
  • Symptoms were CCS class 3 in 23% and CCS class 4 in 14.7%; unstable angina was present in 14.7% and 6.6% of patients had acute myocardial infarction [5].

High impact information on CCS

  • For members of the CCS, laetrile use occurs in a self-help social context where users derive substantial social and emotional support from fellow members [6].
  • We demonstrate here that the CCS-independent activation of mammalian SOD1 involves glutathione, particularly the reduced form, or GSH [7].
  • This CCS-independent activity is evident with both wild-type and mutant variants of SOD1 that have been associated with familial amyotrophic lateral sclerosis [7].
  • A role for glutathione in CCS-independent activation was seen with human SOD1 molecules that were expressed in either yeast cells or immortalized fibroblasts [7].
  • Dose-response studies with a translational blocking agent demonstrate that the cellular oxidative response to O(2) is multitiered: existing apo-pools of SOD1 are activated by CCS in the early response, followed by increasing expression of SOD1 protein with persistent oxidative stress [8].

Chemical compound and disease context of CCS

  • METHODS: Clinical and biochemical niacin status were assessed in a cohort of newly diagnosed carcinoid patients with carcinoid syndrome (CCS, n = 36), carcinoid patients without carcinoid syndrome (CWCS, n = 32) and noncarcinoid controls (n = 24) recruited at two primary care clinics [9].
  • Among patients with a normal chest radiograph who were nonsmokers and not taking an angiotensin converting enzyme inhibitor; CCS was due to PNDS, or asthma, or GERD, or all three in 100% of cases [10].

Biological context of CCS

  • CCS encompasses three protein domains: copper binding Domains I and III at the amino and carboxyl termini, and a central Domain II homologous to SOD1 [11].
  • Importantly, CCS interacts not only with wild-type SOD1 but also with SOD1 containing the common missense mutations resulting in FALS [12].
  • This domain serves as a binding site for at least two proteins, the copper chaperone for superoxide dismutase-1 (CCS), and the Golgi-localized, gamma-ear-containing, ADP ribosylation factor-binding (GGA1) protein, and contains a single phosphorylation site [13].
  • We mapped human CCS to 11q13 (homologous with mouse chromosome 19), utilizing a human x hamster radiation hybrid panel [14].
  • We obtained a 1,174-bp cDNA with an 825-bp open reading frame, translating a 274 amino acid protein that is 86.9% identical to human CCS [14].

Anatomical context of CCS

  • In brain and spinal cord, CCS was found throughout the neuropil, with expression largely confined to neurons and some astrocytes [15].
  • The copper chaperone CCS is abundant in neurons and astrocytes in human and rodent brain [15].
  • In cortical neurons, CCS was present in the soma and proximal dendrites, as well as some axons [15].
  • Like SOD1, CCS immunoreactivity was intense in Purkinje cells, deep cerebellar neurons, and pyramidal cortical neurons, whereas in spinal cord, CCS was highly expressed in motor neurons [15].
  • To elucidate the cell biological mechanisms of this process, SOD1 synthesis and turnover were examined following 64Cu metabolic labeling of fibroblasts derived from CCS+/+ and CCS-/- embryos [16].

Associations of CCS with chemical compounds

  • The X11alpha/CCS interaction was confirmed in coimmunoprecipitation studies plus glutathione S-transferase fusion protein pull-down assays and was shown to be mediated via PDZ2 of X11alpha and a sequence within the carboxyl terminus of domain III of CCS [17].
  • Copper-induced conformational changes in the essential C-terminal peptide of hCCS are consistent with a "pivot, insert, and release" mechanism that is similar to one proposed for the well characterized metal handling enzyme, mercuric ion reductase [18].
  • Our investigation of the cysteine residues that form the disulfide bond in wSOD-1 suggests that the ability of wSODs to readily form this disulfide bond may be the key to obtaining high levels of activation through the CCS-independent pathway [19].
  • The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase [12].
  • Switching cells from copper-deficient to copper-rich medium promoted the rapid degradation of CCS, which could be blocked by the proteosome inhibitors MG132 and lactacystin but not a cysteine protease inhibitor or inhibitors of the lysosomal degradation pathway [20].

Physical interactions of CCS

  • Overexpression of X11alpha inhibited SOD1 activity in transfected Chinese hamster ovary cells which suggests that X11alpha binding to CCS is inhibitory to SOD1 activation [17].

Regulatory relationships of CCS

  • Copper binding to purified yeast CCS induced allosteric conformational changes in Domain III and also enhanced homodimer formation of the polypeptide [21].

Other interactions of CCS

  • The copper chaperone CCS is responsible for copper insertion into apo-SOD1 [22].
  • We have also been able to visualize the co-transport of membranous BACE1 and soluble CCS through axons [23].
  • Aptamer-binding specifically interferes with the recruitment of CCS, but still permits GGA1 association and casein kinase-dependent phosphorylation, consistent with selective binding site targeting within this short peptide [13].
  • The data indicate that copper is rapidly incorporated into both newly synthesized SOD1 and preformed SOD1 apoprotein, that each process is dependent upon CCS and that once incorporated, copper is unavailable for cellular exchange [16].
  • The human copper chaperone for superoxide dismutase (hCCS) delivers the essential copper ion cofactor to copper,zinc superoxide dismutase (SOD1), a key enzyme in antioxidant defense [24].

Analytical, diagnostic and therapeutic context of CCS


  1. The copper chaperone for superoxide dismutase. Culotta, V.C., Klomp, L.W., Strain, J., Casareno, R.L., Krems, B., Gitlin, J.D. J. Biol. Chem. (1997) [Pubmed]
  2. Copper chaperone for Cu,Zn-SOD supplement potentiates the Cu,Zn-SOD function of neuroprotective effects against ischemic neuronal damage in the gerbil hippocampus. Hwang, I.K., Eum, W.S., Yoo, K.Y., Cho, J.H., Kim, D.W., Choi, S.H., Kang, T.C., Kwon, O.S., Kang, J.H., Choi, S.Y., Won, M.H. Free Radic. Biol. Med. (2005) [Pubmed]
  3. Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Watanabe, M., Dykes-Hoberg, M., Culotta, V.C., Price, D.L., Wong, P.C., Rothstein, J.D. Neurobiol. Dis. (2001) [Pubmed]
  4. Expression analysis of genes involved in oxaliplatin response and development of oxaliplatin-resistant HT29 colon cancer cells. Plasencia, C., Martínez-Balibrea, E., Martinez-Cardús, A., Quinn, D.I., Abad, A., Neamati, N. Int. J. Oncol. (2006) [Pubmed]
  5. Clinical results of coronary excimer laser angioplasty: report from the European Coronary Excimer Laser Angioplasty Registry. Baumbach, A., Oswald, H., Kvasnicka, J., Fleck, E., Geschwind, H.J., Ozbek, C., Reifart, N., Bertrand, M.E., Karsch, K.R. Eur. Heart J. (1994) [Pubmed]
  6. Taking laetrile: conversion to medial deviance. Vissing, Y.M., Petersen, J.C. CA: a cancer journal for clinicians. (1981) [Pubmed]
  7. Mechanisms for activating Cu- and Zn-containing superoxide dismutase in the absence of the CCS Cu chaperone. Carroll, M.C., Girouard, J.B., Ulloa, J.L., Subramaniam, J.R., Wong, P.C., Valentine, J.S., Culotta, V.C. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  8. Oxygen and the copper chaperone CCS regulate posttranslational activation of Cu,Zn superoxide dismutase. Brown, N.M., Torres, A.S., Doan, P.E., O'Halloran, T.V. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  9. Biochemical assessment of niacin deficiency among carcinoid cancer patients. Shah, G.M., Shah, R.G., Veillette, H., Kirkland, J.B., Pasieka, J.L., Warner, R.R. Am. J. Gastroenterol. (2005) [Pubmed]
  10. Chronic cough with a history of excessive sputum production. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Smyrnios, N.A., Irwin, R.S., Curley, F.J. Chest (1995) [Pubmed]
  11. Copper activation of superoxide dismutase 1 (SOD1) in vivo. Role for protein-protein interactions with the copper chaperone for SOD1. Schmidt, P.J., Kunst, C., Culotta, V.C. J. Biol. Chem. (2000) [Pubmed]
  12. The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase. Casareno, R.L., Waggoner, D., Gitlin, J.D. J. Biol. Chem. (1998) [Pubmed]
  13. RNA aptamers selectively modulate protein recruitment to the cytoplasmic domain of beta-secretase BACE1 in vitro. Rentmeister, A., Bill, A., Wahle, T., Walter, J., Famulok, M. RNA (2006) [Pubmed]
  14. Cloning and mapping of murine superoxide dismutase copper chaperone (Ccsd) and mapping of the human ortholog. Moore, S.D., Chen, M.M., Cox, D.W. Cytogenet. Cell Genet. (2000) [Pubmed]
  15. The copper chaperone CCS is abundant in neurons and astrocytes in human and rodent brain. Rothstein, J.D., Dykes-Hoberg, M., Corson, L.B., Becker, M., Cleveland, D.W., Price, D.L., Culotta, V.C., Wong, P.C. J. Neurochem. (1999) [Pubmed]
  16. Mechanisms of biosynthesis of mammalian copper/zinc superoxide dismutase. Bartnikas, T.B., Gitlin, J.D. J. Biol. Chem. (2003) [Pubmed]
  17. The neuronal adaptor protein X11alpha interacts with the copper chaperone for SOD1 and regulates SOD1 activity. McLoughlin, D.M., Standen, C.L., Lau, K.F., Ackerley, S., Bartnikas, T.P., Gitlin, J.D., Miller, C.C. J. Biol. Chem. (2001) [Pubmed]
  18. Mechanism of Cu,Zn-superoxide dismutase activation by the human metallochaperone hCCS. Rae, T.D., Torres, A.S., Pufahl, R.A., O'Halloran, T.V. J. Biol. Chem. (2001) [Pubmed]
  19. Activation of CuZn superoxide dismutases from Caenorhabditis elegans does not require the copper chaperone CCS. Jensen, L.T., Culotta, V.C. J. Biol. Chem. (2005) [Pubmed]
  20. Copper modulates the degradation of copper chaperone for Cu,Zn superoxide dismutase by the 26 S proteosome. Bertinato, J., L'Abbé, M.R. J. Biol. Chem. (2003) [Pubmed]
  21. Multiple protein domains contribute to the action of the copper chaperone for superoxide dismutase. Schmidt, P.J., Rae, T.D., Pufahl, R.A., Hamma, T., Strain, J., O'Halloran, T.V., Culotta, V.C. J. Biol. Chem. (1999) [Pubmed]
  22. Solution structure of the second PDZ domain of the neuronal adaptor X11alpha and its interaction with the C-terminal peptide of the human copper chaperone for superoxide dismutase. Duquesne, A.E., Ruijter, M., Brouwer, J., Drijfhout, J.W., Nabuurs, S.B., Spronk, C.A., Vuister, G.W., Ubbink, M., Canters, G.W. J. Biomol. NMR (2005) [Pubmed]
  23. BACE1 cytoplasmic domain interacts with the copper chaperone for superoxide dismutase-1 and binds copper. Angeletti, B., Waldron, K.J., Freeman, K.B., Bawagan, H., Hussain, I., Miller, C.C., Lau, K.F., Tennant, M.E., Dennison, C., Robinson, N.J., Dingwall, C. J. Biol. Chem. (2005) [Pubmed]
  24. Crystal structure of the second domain of the human copper chaperone for superoxide dismutase. Lamb, A.L., Wernimont, A.K., Pufahl, R.A., O'Halloran, T.V., Rosenzweig, A.C. Biochemistry (2000) [Pubmed]
  25. Copper stabilizes a heterodimer of the yCCS metallochaperone and its target superoxide dismutase. Torres, A.S., Petri, V., Rae, T.D., O'Halloran, T.V. J. Biol. Chem. (2001) [Pubmed]
  26. Aggregate formation in Cu,Zn superoxide dismutase-related proteins. Son, M., Cloyd, C.D., Rothstein, J.D., Rajendran, B., Elliott, J.L. J. Biol. Chem. (2003) [Pubmed]
  27. Coupled cluster and density functional theory studies of the vibrational contribution to the optical rotation of (S)-propylene oxide. Kongsted, J., Pedersen, T.B., Jensen, L., Hansen, A.E., Mikkelsen, K.V. J. Am. Chem. Soc. (2006) [Pubmed]
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