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ATP7B  -  ATPase, Cu++ transporting, beta polypeptide

Homo sapiens

Synonyms: Copper pump 2, Copper-transporting ATPase 2, PWD, WC1, WD, ...
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Disease relevance of ATP7B

  • Mutations in ATP7B lead to Wilson's disease, a severe disorder with neurological and hepatic manifestations [1].
  • In this study, the cDNAs derived from a normal human ATP7A gene and the murine ATP7B homologue, Atp7b, were separately transfected into an immortalized fibroblast cell line obtained from a Menkes' disease patient [2].
  • The Wilson protein (ATP7B) is a copper-transporting CPx-type ATPase defective in the copper toxicity disorder Wilson disease [3].
  • Therefore, we characterized the subcellular localization of normal and mutant ATP7B in human livers and in hepatoma cell lines [4].
  • RESULTS: A variable degree of cytoplasmic staining of ATP7B in tumor cells was observed in 34.6% (36 of 104 cases) of the analyzed carcinomas [5].

Psychiatry related information on ATP7B

  • OBJECTIVE: To examine the effects of an 8-week cognitive-behavioral (C-B) intervention tailored to the specific deficits of persons with dementia (PWDs) on selected outcomes for homebound caregivers and the functional status of the PWD [6].

High impact information on ATP7B

  • We have previously reported the cloning of a gene that encodes a copper transporting P-type ATPase (ATP7B) which is defective in Wilson disease [7].
  • The aim of this study was to clarify the mechanism underlying ATP7B-mediated copper detoxification by investigating endogenous ATP7B localization in the HepG2 hepatoma cell line and its ability to mediate vesicular sequestration of excess intracellular copper [8].
  • Mutation of an endocytic retrieval signal in ATP7B caused the protein to constitutively localize to vesicles and not to the plasma membrane, suggesting that a vesicular compartment(s) is the final trafficking destination for ATP7B [8].
  • Expression of wild-type and mutant ATP7B caused Chinese hamster ovary cells to accumulate copper in vesicles, which subsequently undergo exocytosis, releasing copper across the plasma membrane [8].
  • The association of ClC-4 and the Wilson's disease protein (ATP7B) was determined by co-immunoprecipitation [9].

Chemical compound and disease context of ATP7B

  • We further predict that drugs targeting ATP7B might be useful in combination with cisplatin-based regimen for the improvement of patients with ovarian carcinoma [5].
  • The influence of these transporters on the pharmacodynamics of cisplatin, carboplatin, and oxaliplatin was investigated using human Menkes' disease fibroblasts (Me32a) that do not express either transporter and sublines molecularly engineered to express either ATP7A (MeMNK) or ATP7B (MeWND) [10].
  • This is the first report to show that a copper-transporting P-type adenosine triphosphatase, ATP7B, is expressed in certain breast carcinomas, and a priori knowledge of its expression is important for the choice of therapy [11].
  • In ATP7B, the Wilson disease protein, the N-terminal domain is made up of six metal-binding sub-domains containing the MXCXXC motif which is known to coordinate copper via the two cysteine residues [12].
  • Another cell line, CuR 41, showed increased basal expression of MT and ATP7B mRNA but not ATP7B protein, and resistance to cadmium and zinc toxicity [13].

Biological context of ATP7B


Anatomical context of ATP7B

  • When hepatocytes are exposed to elevated copper levels, ATP7B traffics from the trans-Golgi network toward the biliary canalicular membrane to excrete excess copper into bile [14].
  • Thus, defective copper ATPase activity of ATP7B in the late endosomes appears to be the main defect of Wilson disease [19].
  • The dynactin complex binds cargo, such as vesicles and organelles, to cytoplasmic dynein for retrograde microtubule-mediated trafficking and could feasibly be involved in the copper-regulated trafficking of ATP7B [14].
  • ATP7B appears to translocate copper from the cytosol to the late endosomal lumen, thus participating in biliary copper excretion via lysosomes [19].
  • We examined the distribution of ATP7B using an anti-ATP7B antibody, green fluorescent protein (GFP)-ATP7B (GFP-ATP7B) and ATP7B-DsRed in various cultured cells [19].

Associations of ATP7B with chemical compounds

  • U18666A induced the formation of late endosome-lysosome hybrid organelles, with GFP-ATP7B localized with NPC1 in these structures [19].
  • Treatment with copper sulfate did not affect the localization of ATP7B [20].
  • Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B [10].
  • Fusion of the NH2-terminal 63 AA of ATP7B to the truncated protein restored both its Cu responsiveness and correct intracellular targeting [21].
  • Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma [11].

Physical interactions of ATP7B

  • We have used isothermal titration calorimetry to measure the association constant (K(a)) and stoichiometry (n) values of Cu(I) binding to the WND metal-binding domains and to their metallochaperone Atox1 [22].
  • Four WD patient-derived mutations in this region of ATP7B significantly increased its binding to COMMD1 [23].

Co-localisations of ATP7B


Regulatory relationships of ATP7B

  • Our data also suggest that Atox1 can regulate the copper occupancy of WNDP [24].

Other interactions of ATP7B

  • On Western blot analysis all three resistant lines exhibited increased expression of one or the other of the two copper export pumps (ATP7A or ATP7B) with no change in the HAH1 chaperone [25].
  • In addition, we speculate on how copper binding may regulate the activity and intracellular distribution of WNDP, and what role the human copper chaperone Atox1 may play in these processes [16].
  • The distribution of ATP7B was compared with that of Rab7 and Niemann-Pick C1 (NPC1), proteins that localize in the late endosomes [19].
  • ATP4B lies in 13q34 and is separated from ATP7B by several loci whose mouse homologues map to mouse chromosome 14 [26].
  • The MURR1 gene was identified recently, and it was hypothesized that this gene is also essential for biliary Cu excretion and is presumed to act downstream of ATP7B [27].

Analytical, diagnostic and therapeutic context of ATP7B

  • Using site-directed mutagenesis, we mutated or deleted various combinations of the MBSs and assessed the effect of these changes on the localization and trafficking of ATP7B [3].
  • In this study, the expression and localization of the MNK and WND proteins in the human placenta were investigated in detail using immunoperoxidase and double-label immunohistochemistry [28].
  • METHODS: Immunofluorescence microscopy was used to investigate the effect of copper concentration on the localization of endogenous ATP7B in HepG2 cells [8].
  • In addition, 14 ATP7B mutants tagged to green fluorescent protein were generated and expressed in HuH-7 and HepG2 cells; intracellular localization of these mutants was characterized by confocal microscopy [4].
  • METHODS: Subcellular distribution of ATP7B in liver tissue from 3 control individuals and 3 Wilson's disease patients harboring a homozygous H1069Q-ATP7B mutation was analyzed by using immunogold electron microscopy [4].


  1. The role of the invariant His-1069 in folding and function of the Wilson's disease protein, the human copper-transporting ATPase ATP7B. Tsivkovskii, R., Efremov, R.G., Lutsenko, S. J. Biol. Chem. (2003) [Pubmed]
  2. Correction of the copper transport defect of Menkes patient fibroblasts by expression of the Menkes and Wilson ATPases. La Fontaine, S.L., Firth, S.D., Camakaris, J., Englezou, A., Theophilos, M.B., Petris, M.J., Howie, M., Lockhart, P.J., Greenough, M., Brooks, H., Reddel, R.R., Mercer, J.F. J. Biol. Chem. (1998) [Pubmed]
  3. Intracellular trafficking of the human Wilson protein: the role of the six N-terminal metal-binding sites. Cater, M.A., Forbes, J., La Fontaine, S., Cox, D., Mercer, J.F. Biochem. J. (2004) [Pubmed]
  4. Defective cellular localization of mutant ATP7B in Wilson's disease patients and hepatoma cell lines. Huster, D., Hoppert, M., Lutsenko, S., Zinke, J., Lehmann, C., Mössner, J., Berr, F., Caca, K. Gastroenterology (2003) [Pubmed]
  5. Prognostic value of the Cu-transporting ATPase in ovarian carcinoma patients receiving cisplatin-based chemotherapy. Nakayama, K., Kanzaki, A., Terada, K., Mutoh, M., Ogawa, K., Sugiyama, T., Takenoshita, S., Itoh, K., Yaegashi, N., Miyazaki, K., Neamati, N., Takebayashi, Y. Clin. Cancer Res. (2004) [Pubmed]
  6. Cognitive-behavioral intervention for homebound caregivers of persons with dementia. Chang, B.L. Nursing research. (1999) [Pubmed]
  7. The Wilson disease gene: spectrum of mutations and their consequences. Thomas, G.R., Forbes, J.R., Roberts, E.A., Walshe, J.M., Cox, D.W. Nat. Genet. (1995) [Pubmed]
  8. ATP7B mediates vesicular sequestration of copper: insight into biliary copper excretion. Cater, M.A., La Fontaine, S., Shield, K., Deal, Y., Mercer, J.F. Gastroenterology (2006) [Pubmed]
  9. Involvement of chloride channels in hepatic copper metabolism: ClC-4 promotes copper incorporation into ceruloplasmin. Wang, T., Weinman, S.A. Gastroenterology (2004) [Pubmed]
  10. Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B. Samimi, G., Katano, K., Holzer, A.K., Safaei, R., Howell, S.B. Mol. Pharmacol. (2004) [Pubmed]
  11. Copper-transporting P-type adenosine triphosphatase (ATP7B) is expressed in human breast carcinoma. Kanzaki, A., Toi, M., Neamati, N., Miyashita, H., Oubu, M., Nakayama, K., Bando, H., Ogawa, K., Mutoh, M., Mori, S., Terada, K., Sugiyama, T., Fukumoto, M., Takebayashi, Y. Jpn. J. Cancer Res. (2002) [Pubmed]
  12. Copper transfer to the N-terminal domain of the Wilson disease protein (ATP7B): X-ray absorption spectroscopy of reconstituted and chaperone-loaded metal binding domains and their interaction with exogenous ligands. Ralle, M., Lutsenko, S., Blackburn, N.J. J. Inorg. Biochem. (2004) [Pubmed]
  13. Copper resistant human hepatoblastoma mutant cell lines without metallothionein induction overexpress ATP7B. Schilsky, M.L., Stockert, R.J., Kesner, A., Gorla, G.R., Gagliardi, G.S., Terada, K., Miura, N., Czaja, M.J. Hepatology (1998) [Pubmed]
  14. Copper-dependent interaction of dynactin subunit p62 with the N terminus of ATP7B but not ATP7A. Lim, C.M., Cater, M.A., Mercer, J.F., La Fontaine, S. J. Biol. Chem. (2006) [Pubmed]
  15. A comparison of the mutation spectra of Menkes disease and Wilson disease. Hsi, G., Cox, D.W. Hum. Genet. (2004) [Pubmed]
  16. Human copper-transporting ATPase ATP7B (the Wilson's disease protein): biochemical properties and regulation. Lutsenko, S., Efremov, R.G., Tsivkovskii, R., Walker, J.M. J. Bioenerg. Biomembr. (2002) [Pubmed]
  17. Identification and analysis of mutations in the Wilson disease gene (ATP7B): population frequencies, genotype-phenotype correlation, and functional analyses. Shah, A.B., Chernov, I., Zhang, H.T., Ross, B.M., Das, K., Lutsenko, S., Parano, E., Pavone, L., Evgrafov, O., Ivanova-Smolenskaya, I.A., Annerén, G., Westermark, K., Urrutia, F.H., Penchaszadeh, G.K., Sternlieb, I., Scheinberg, I.H., Gilliam, T.C., Petrukhin, K. Am. J. Hum. Genet. (1997) [Pubmed]
  18. Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups. Kalinsky, H., Funes, A., Zeldin, A., Pel-Or, Y., Korostishevsky, M., Gershoni-Baruch, R., Farrer, L.A., Bonne-Tamir, B. Hum. Mutat. (1998) [Pubmed]
  19. The Wilson disease protein ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein. Harada, M., Kawaguchi, T., Kumemura, H., Terada, K., Ninomiya, H., Taniguchi, E., Hanada, S., Baba, S., Maeyama, M., Koga, H., Ueno, T., Furuta, K., Suganuma, T., Sugiyama, T., Sata, M. Am. J. Pathol. (2005) [Pubmed]
  20. Wilson disease protein ATP7B is localized in the late endosomes in a polarized human hepatocyte cell line. Harada, M., Kumemura, H., Sakisaka, S., Shishido, S., Taniguchi, E., Kawaguchi, T., Hanada, S., Koga, H., Kumashiro, R., Ueno, T., Suganuma, T., Furuta, K., Namba, M., Sugiyama, T., Sata, M. Int. J. Mol. Med. (2003) [Pubmed]
  21. NH2-terminal signals in ATP7B Cu-ATPase mediate its Cu-dependent anterograde traffic in polarized hepatic cells. Guo, Y., Nyasae, L., Braiterman, L.T., Hubbard, A.L. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  22. Binding of copper(I) by the Wilson disease protein and its copper chaperone. Wernimont, A.K., Yatsunyk, L.A., Rosenzweig, A.C. J. Biol. Chem. (2004) [Pubmed]
  23. Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B. de Bie, P., van de Sluis, B., Burstein, E., van de Berghe, P.V., Muller, P., Berger, R., Gitlin, J.D., Wijmenga, C., Klomp, L.W. Gastroenterology (2007) [Pubmed]
  24. Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson's disease protein and regulates its catalytic activity. Walker, J.M., Tsivkovskii, R., Lutsenko, S. J. Biol. Chem. (2002) [Pubmed]
  25. Acquisition of resistance to cisplatin is accompanied by changes in the cellular pharmacology of copper. Katano, K., Kondo, A., Safaei, R., Holzer, A., Samimi, G., Mishima, M., Kuo, Y.M., Rochdi, M., Howell, S.B. Cancer Res. (2002) [Pubmed]
  26. Mapping of the mouse homologue of the Wilson disease gene to mouse chromosome 8. Reed, V., Williamson, P., Bull, P.C., Cox, D.W., Boyd, Y. Genomics (1995) [Pubmed]
  27. Molecular regulation of copper excretion in the liver. Wijmenga, C., Klomp, L.W. The Proceedings of the Nutrition Society. (2004) [Pubmed]
  28. Expression and localization of menkes and Wilson copper transporting ATPases in human placenta. Hardman, B., Manuelpillai, U., Wallace, E.M., van de Waasenburg, S., Cater, M., Mercer, J.F., Ackland, M.L. Placenta (2004) [Pubmed]
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