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Gene Review

ATP7A  -  ATPase, Cu++ transporting, alpha polypeptide

Homo sapiens

Synonyms: Copper pump 1, Copper-transporting ATPase 1, DSMAX, MC1, MK, ...
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Disease relevance of ATP7A


Psychiatry related information on ATP7A

  • Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment [6].
  • The MC1-induced anti-Id response (Ab-3) in both mice and rabbits expressed a similar Id with the Ab-1, which is not normally expressed in the anti-gp41 peptide antibody response induced by the nominal antigen in Balb/c mice and in rabbits [7].
  • CONCLUSION: Exposure variables, chronic diseases, alcohol consumption, and sedative use contribute to educational inequalities in traffic and OHS injuries resulting in hospital admission [8].
  • METHODS: Data came from two contemporaneous surveys, the National Comorbidity Survey (NCS; N=6780) and the Mental Health Supplement of the Ontario Health Survey (OHS-MHS; N=7001) [9].
  • This study examined whether conformational changes detected by antibodies MC1 and TG3 represent early abnormalities in the disease process by assessing their presence at different stages of dementia in multiple brain regions [10].

High impact information on ATP7A

  • Human Menkes disease and the murine Mottled phenotype are X-linked diseases that result from copper deficiency due to mutations in a copper-effluxing ATPase, designated ATP7A [11].
  • Mutations in the genes encoding the major fibrillar collagen types I and III have been demonstrated in EDS types VII and IV, respectively, while mutations in the lysyl hydroxylase and ATP7A genes, with roles in collagen cross-linking, are responsible for EDS types VI and IX [12].
  • 3. On yeast artificial chromosomes from this region we have identified a sequence, similar to that coding for the proposed copper binding regions of the putative ATPase gene (MNK) defective in Menkes disease [13].
  • The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene [14].
  • Among these, expression analysis of UHRF1, ATP7A, and aldehyde oxidase 1 in combination could potentially provide a useful additional diagnostic tool for fine-needle aspirated or cytological specimens obtained during endoscopic investigations [15].

Chemical compound and disease context of ATP7A


Biological context of ATP7A

  • These findings indicate that the presence of barely detectable amounts of correctly spliced ATP7A transcript is sufficient to permit the development of the milder OHS phenotype, as opposed to classic MD [20].
  • More than 150 point mutations have now been identified in the ATP7A gene [20].
  • In contrast to previously reported cases of OHS, we describe a case of OHS in which, because of a frameshift mutation, no normal ATP7A is produced [1].
  • In this study we show that ATP7A is internalized by a novel pathway that is independent of clathrin-mediated endocytosis [21].
  • ATP7A is a P-type ATPase involved in copper(I) homeostasis in humans [22].

Anatomical context of ATP7A

  • It has been demonstrated that the dileucine motif L1487L1488 functions as an endocytic signal for ATP7A cycling between the TGN and the plasma membrane [1].
  • Data suggest that steady-state localization of ATP7A to the trans-Golgi network (TGN) is necessary for proper activity of lysyl oxidase, which is the predominant cuproenzyme whose activity is deficient in OHS and which is essential for maintenance of connective-tissue integrity [1].
  • These findings define a novel route required for ATP7A internalization and delivery to endosomes [21].
  • The Menkes disease gene encodes a P-type transmembrane ATPase (ATP7A) that translocates cytosolic copper ions across intracellular membranes of compartments along the secretory pathway [21].
  • These findings indicate that endoplasmic reticulum localization only of a variant ATP7A protein is insufficient to effect normal copper transport [23].

Associations of ATP7A with chemical compounds

  • We have generated polyclonal antibodies against the amino-terminal third of the Menkes protein (ATP7A; MNK) by immunizing rabbits with a histidine-tagged MNK fusion construct containing metal-binding domains 1-4 [24].
  • Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B [16].
  • The 2008 and 2008/JM118 cells did not differ in their uptake or efflux of (64)Cu, expression of Cu efflux transporters ATP7A or ATP7B or their glutathione content [25].
  • A point mutation (T to C) that results in substitution of proline for serine in a putative eighth transmembrane domain of the ATP7A was identified [26].
  • Compared to ATP7A, the rat transcript coded for an additional alanine (A446) in the heavy metal binding (Hmb) domain and showed a 34 bp gap in the 3' UTR [27].

Physical interactions of ATP7A

  • ATOX1 is a cytoplasmic copper chaperone that interacts with the copper-binding domain of the membrane copper transporters ATP7A and ATP7B [28].
  • We propose a change in name for this protein from PISP (plasma membrane calcium ATPase-interacting single-PDZ protein) to AIPP1 (ATPase-interacting PDZ protein) and suggest that it represents the protein that interacts with the class I PDZ binding motif identified at the ATP7A C terminus [29].

Other interactions of ATP7A

  • 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 [30].
  • Atx1 and ATOX1 both contain an MXCXXC motif that is also present in Ccc2 (two motifs) and ATP7A/B (six motifs) [31].
  • Although delivery of copper to lumenal cuproproteins like PAM involves ATP7A, lumenal chaperones may not be required [32].
  • In contrast, expression of a constitutively active mutant of the Rac1 GTPase inhibits plasma membrane internalization of both the ATP7A and transferrin receptor transmembrane proteins [21].
  • Copper-dependent interaction of dynactin subunit p62 with the N terminus of ATP7B but not ATP7A [33].

Analytical, diagnostic and therapeutic context of ATP7A


  1. A novel frameshift mutation in exon 23 of ATP7A (MNK) results in occipital horn syndrome and not in Menkes disease. Dagenais, S.L., Adam, A.N., Innis, J.W., Glover, T.W. Am. J. Hum. Genet. (2001) [Pubmed]
  2. Copper transporting P-type ATPases and human disease. Cox, D.W., Moore, S.D. J. Bioenerg. Biomembr. (2002) [Pubmed]
  3. Solution structure of the N-domain of Wilson disease protein: distinct nucleotide-binding environment and effects of disease mutations. Dmitriev, O., Tsivkovskii, R., Abildgaard, F., Morgan, C.T., Markley, J.L., Lutsenko, S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  4. Modulation of the cellular pharmacology of JM118, the major metabolite of satraplatin, by copper influx and efflux transporters. Samimi, G., Howell, S.B. Cancer Chemother. Pharmacol. (2006) [Pubmed]
  5. Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells. Song, I.S., Savaraj, N., Siddik, Z.H., Liu, P., Wei, Y., Wu, C.J., Kuo, M.T. Mol. Cancer Ther. (2004) [Pubmed]
  6. Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment. Niciu, M.J., Ma, X.M., El Meskini, R., Ronnett, G.V., Mains, R.E., Eipper, B.A. Neuroscience (2006) [Pubmed]
  7. Administration of noninternal image monoclonal anti-idiotypic antibodies induces idiotype-restricted responses specific for human immunodeficiency virus envelope glycoprotein epitopes. Zhou, E.M., Lohman, K.L., Kennedy, R.C. Virology (1990) [Pubmed]
  8. Education was associated with injuries requiring hospital admission. van Lenthe, F.J., van Beeck, E.F., Gevers, E., Mackenbach, J.P. Journal of clinical epidemiology. (2004) [Pubmed]
  9. Does a U-shaped relationship exist between alcohol use and DSM-III-R mood and anxiety disorders? Sareen, J., McWilliams, L., Cox, B., Stein, M.B. Journal of affective disorders. (2004) [Pubmed]
  10. Tau protein abnormalities associated with the progression of alzheimer disease type dementia. Haroutunian, V., Davies, P., Vianna, C., Buxbaum, J.D., Purohit, D.P. Neurobiol. Aging (2007) [Pubmed]
  11. A murine model of Menkes disease reveals a physiological function of metallothionein. Kelly, E.J., Palmiter, R.D. Nat. Genet. (1996) [Pubmed]
  12. A translocation interrupts the COL5A1 gene in a patient with Ehlers-Danlos syndrome and hypomelanosis of Ito. Toriello, H.V., Glover, T.W., Takahara, K., Byers, P.H., Miller, D.E., Higgins, J.V., Greenspan, D.S. Nat. Genet. (1996) [Pubmed]
  13. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Bull, P.C., Thomas, G.R., Rommens, J.M., Forbes, J.R., Cox, D.W. Nat. Genet. (1993) [Pubmed]
  14. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Tanzi, R.E., Petrukhin, K., Chernov, I., Pellequer, J.L., Wasco, W., Ross, B., Romano, D.M., Parano, E., Pavone, L., Brzustowicz, L.M. Nat. Genet. (1993) [Pubmed]
  15. Proteomic analysis of chronic pancreatitis and pancreatic adenocarcinoma. Crnogorac-Jurcevic, T., Gangeswaran, R., Bhakta, V., Capurso, G., Lattimore, S., Akada, M., Sunamura, M., Prime, W., Campbell, F., Brentnall, T.A., Costello, E., Neoptolemos, J., Lemoine, N.R. Gastroenterology (2005) [Pubmed]
  16. 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]
  17. Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells. Samimi, G., Safaei, R., Katano, K., Holzer, A.K., Rochdi, M., Tomioka, M., Goodman, M., Howell, S.B. Clin. Cancer Res. (2004) [Pubmed]
  18. Copper-replacement treatment for symptomatic Menkes disease: ethical considerations. Sheela, S.R., Latha, M., Liu, P., Lem, K., Kaler, S.G. Clin. Genet. (2005) [Pubmed]
  19. Equilibrium binding studies of non-claret disjunctional protein (Ncd) reveal cooperative interactions between the motor domains. Foster, K.A., Correia, J.J., Gilbert, S.P. J. Biol. Chem. (1998) [Pubmed]
  20. Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome. Møller, L.B., Tümer, Z., Lund, C., Petersen, C., Cole, T., Hanusch, R., Seidel, J., Jensen, L.R., Horn, N. Am. J. Hum. Genet. (2000) [Pubmed]
  21. The Menkes disease ATPase (ATP7A) is internalized via a Rac1-regulated, clathrin- and caveolae-independent pathway. Cobbold, C., Coventry, J., Ponnambalam, S., Monaco, A.P. Hum. Mol. Genet. (2003) [Pubmed]
  22. A NMR study of the interaction of a three-domain construct of ATP7A with copper(I) and copper(I)-HAH1: the interplay of domains. Banci, L., Bertini, I., Cantini, F., Chasapis, C.T., Hadjiliadis, N., Rosato, A. J. Biol. Chem. (2005) [Pubmed]
  23. Constitutive skipping of alternatively spliced exon 10 in the ATP7A gene abolishes Golgi localization of the menkes protein and produces the occipital horn syndrome. Qi, M., Byers, P.H. Hum. Mol. Genet. (1998) [Pubmed]
  24. Immunocytochemical localization of the Menkes copper transport protein (ATP7A) to the trans-Golgi network. Dierick, H.A., Adam, A.N., Escara-Wilke, J.F., Glover, T.W. Hum. Mol. Genet. (1997) [Pubmed]
  25. Novel mechanisms of platinum drug resistance identified in cells selected for resistance to JM118 the active metabolite of satraplatin. Samimi, G., Kishimoto, S., Manorek, G., Breaux, J.K., Howell, S.B. Cancer Chemother. Pharmacol. (2007) [Pubmed]
  26. A serine-to-proline mutation in the copper-transporting P-type ATPase gene of the macular mouse. Mori, M., Nishimura, M. Mamm. Genome (1997) [Pubmed]
  27. Sequence of a Menkes-type Cu-transporting ATPase from rat C6 glioma cells: comparison of the rat protein with other mammalian Cu-transporting ATPases. Qian, Y., Tiffany-Castiglioni, E., Harris, E.D. Mol. Cell. Biochem. (1998) [Pubmed]
  28. Tissue localization of the copper chaperone ATOX1 and its potential role in disease. Moore, S.D., Helmle, K.E., Prat, L.M., Cox, D.W. Mamm. Genome (2002) [Pubmed]
  29. A single PDZ domain protein interacts with the Menkes copper ATPase, ATP7A. A new protein implicated in copper homeostasis. Stephenson, S.E., Dubach, D., Lim, C.M., Mercer, J.F., La Fontaine, S. J. Biol. Chem. (2005) [Pubmed]
  30. 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]
  31. Copper-dependent protein-protein interactions studied by yeast two-hybrid analysis. van Dongen, E.M., Klomp, L.W., Merkx, M. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  32. Supplying copper to the cuproenzyme peptidylglycine alpha-amidating monooxygenase. El Meskini, R., Culotta, V.C., Mains, R.E., Eipper, B.A. J. Biol. Chem. (2003) [Pubmed]
  33. 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]
  34. Multiple transcripts coding for the menkes gene: evidence for alternative splicing of Menkes mRNA. Reddy, M.C., Harris, E.D. Biochem. J. (1998) [Pubmed]
  35. Copper exposure induces trafficking of the menkes protein in intestinal epithelium of ATP7A transgenic mice. Monty, J.F., Llanos, R.M., Mercer, J.F., Kramer, D.R. J. Nutr. (2005) [Pubmed]
  36. X-linked recessive Menkes disease: identification of partial gene deletions in affected males. Poulsen, L., Horn, N., Heilstrup, H., Lund, C., Tümer, Z., Møller, L.B. Clin. Genet. (2002) [Pubmed]
  37. An NMR study of the interaction between the human copper(I) chaperone and the second and fifth metal-binding domains of the Menkes protein. Banci, L., Bertini, I., Ciofi-Baffoni, S., Chasapis, C.T., Hadjiliadis, N., Rosato, A. FEBS J. (2005) [Pubmed]
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