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Title: Atp7a  
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Subject: Wilson disease protein, P-type ATPase, ATPase, Calcium ATPase, Hydrogen potassium ATPase
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ATPase, Cu++ transporting, alpha polypeptide
PDB rendering based on 1aw0.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; DSMAX; MK; MNK; SMAX3
External IDs GeneCards:
EC number
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

ATP7A, also known as Menkes’ protein (MNK), is a copper-transporting P-type ATPase which uses the energy arising from ATP hydrolysis to transport Cu(I) across cell membranes. The ATP7A protein is a transmembrane protein and is expressed in the intestine and all tissues except liver. In the intestine, ATP7A regulates Cu(I) absorption in the human body by transporting Cu(I) from the small intestine into the blood. In other tissues, ATP7A shuttles between the Golgi apparatus and the cell membrane to maintain proper Cu(I) concentrations (since there is no free Cu(I) in the cell, Cu(I) ions are all tightly bound) in the cell and provides certain enzymes with Cu(I) (e.g. peptidyl-α-monooxygenase, tyrosinase, and lysyl oxidase). The X-linked, inherited, lethal genetic disorder of the ATP7A gene causes Menkes disease, a copper deficiency resulting in early childhood death.[1]


  • Gene 1
  • Structure 2
  • Conformational change 3
  • Transport mechanism 4
  • Function 5
  • Interactions 6
  • Clinical significance 7
  • Inhibition 8
  • References 9
  • Further reading 10
  • External links 11


The ATP7A gene is located on the long (q) arm of the X chromosome between at position 13.3. The encoded ATP7A protein has 1,500 amino acids.[2] Mutations/additions/deletions of this gene often cause copper deficiency, which leads to progressive neurodegeneration and death in children.[3]


ATP7A is a transmembrane protein with the N- and C-termini both oriented towards the cytosol (see picture). It is highly homologous to protein ATP7B. ATP7A contains three major functional domains:[4][5][6][7]

  1. Eight transmembrane segments that form a channel and allow for Cu(I) to pass through the membrane;
  2. An ATP-binding domain;
  3. A large N-terminal cytosolic domain that contains six repeated Cu(I)-binding sites, each containing a GMTCXXC motif.
Proposed structure of copper-transporting protein ATP7A

Many motifs in the ATP7A structure are conserved:[6]

  • The TGEA motif lies in the loop on the cytosolic side between transmembrane segments 4 and 5 and is involved in energy transfer.
  • The CPC motif located in transmembrane segment 6 is common for all heavy metal transporting ATPases.

Between transmembrane segments 6 and 7 is a large cytoplasmic loop, where three motifs are located: DKTG, SEHPL, and GDGXND.

  • The DKTG motif is essential for the proper function of the ATPase. The aspartic acid (D) residue is phosphorylated during the transport cycles.
  • The SEHPL motif only exists in heavy metal transporting P-type ATPases. Without the histidine (H) residue ATP7A may not function properly.
  • The GDGXND motif near transmembrane segment 7 is thought to contain mainly α-helices and serves as a structural support.

The six Cu(I)-binding sites at the N-terminal bind one Cu(I) each. This binding site is not specific for Cu(I) and can bind various transition metal ions. Cd(II), Au(III) and Hg(II) bind to the binding site more tightly than does Zn(II), whereas Mn(II) and Ni(II) have lower affinities relative to Zn(II). In the case of Cu(I), a possible cooperative-binding mechanism is observed. When the Cu(I) concentration is low, Cu(I) has a lower affinity for ATP7A compared to Zn(II); as the Cu(I) concentration increases, a dramatic increasing affinity of Cu(I) for the protein is observed.[6]

Conformational change

The two cysteine (C) residues in each Cu(I)-binding site are coordinated to Cu(I) with a S-Cu(I)-S angle between 120 and 180° and a Cu-S distance of 2.16 Å. Experimental results from a homologous protein ATP7B suggests that reducing reagents are involved, and upon Cu(I) binding the disulfide bonding between the cysteine residues is broken as cysteine starts to bind to Cu(I), leading to a series of conformational changes at the N-terminal of the protein, and possibly activating the Cu(I)-transporting activity of other cytosolic loops.[6]

Of the six copper(I)-binding sites, two are considered enough for the function of Cu(I) transport. The reason why there are six binding sites remains not fully understood. However, some scientists have proposed that the other four sites may serve as a Cu(I) concentration detector.[4]

Transport mechanism

ATP7A belongs to a transporter family called P-type ATPases, which catalyze auto-phosphorylation of a key conserved aspartic acid (D) residue within the enzyme. The first step is ATP binding to the ATP-binding domain and Cu(I) binding to the transmembrane region. Then ATP7A is phosphorylated at the key aspartic acid (D) residue in the highly conserved DKTG motif, accompanied by Cu(I) release. A subsequent dephosphorylation of the intermediate finishes the catalytic cycle. Within each cycle, ATP7A interconverts between at least two different conformations, E1 and E2. In the E1 state, Cu(I) is tightly bound to the binding sites on the cytoplasmic side; in the E2 state, the affinity of ATP7A for Cu(I) decreases and Cu(I) is released on the extracellular side.[8]


ATP7A is important for regulating copper Cu(I) in mammals.[5] This protein is found in most tissues, but it is not expressed in the liver.[6] In the small intestine, the ATP7A protein helps control the absorption of Cu(I) from food. After Cu(I) ions are absorbed into enterocytes, ATP7A is required to transfer them across the basolateral membrane into the circulation.[4]

In other organs and tissues, the ATP7A protein has a dual role and shuttles between two locations within the cell. The protein normally resides in a cell structure called the Golgi apparatus, which modifies and transports newly produced enzymes and other proteins. Here, ATP7A supplies Cu(I) to certain enzymes (e.g. peptidyl-α-monooxygenase, tyrosinase, and lysyl oxidase[4]) that are critical for the structures and functions of brain, bone, skin, hair, connective tissue, and the nervous system. If Cu(I) levels in the cell environment are elevated, however, ATP7A moves to the cell membrane and eliminates excess Cu(I) from the cell.[3][5]

The functions of ATP7A in some tissues of the human body are as follows:[5]

Tissue Location Function
Kidney Expressed in epithelial cells of the proximal and distal renal tubules Removes excess Cu(I) to maintain Cu(I) level in the kidney
Parenchyma In the cytotrophoblast, syncytiotrophoblast and foetal vascular endothelial cells Delivers Cu(I) to placental cuproenzymes and transports Cu(I) into the foetal circulation
Central nervous system Various locations Distributes Cu(I) in the various compartments of the central nervous system


ATP7A has been shown to interact with ATOX1 and GLRX. Antioxidant 1 copper chaperone (ATOX1) is required to maintain Cu(I) copper homeostasis in the cell. It can bind and transport cytosolic Cu(I) to ATP7A in the trans-Golgi-network. Glutaredoxin-1 (GRX1) has is also essential for ATP7A function. It promotes Cu(I) binding for subsequent transport by catalyzing the reduction of disulfide bridges. It may also catalyze de-glutathionylation reaction of the C (cysteine) residues within the six Cu(I)-binding motifs GMTCXXC.[5]

Clinical significance

Menkes disease is caused by mutations in the ATP7A gene. Researchers have identified different ATP7A mutations that cause Menkes disease and occipital horn syndrome (OHS), the milder form of Menkes disease. Many of these mutations delete part of the gene and are predicted to produce a shortened ATP7A protein that is unable to transport Cu(I). Other mutations insert additional DNA base pairs or use the wrong base pairs, which leads to ATP7A proteins that do not function properly.[2]

The altered proteins that result from ATP7A mutations impair the absorption of copper from food, fail to supply copper to certain enzymes, or get stuck in the cell membrane, unable to shuttle back and forth from the Golgi. As a result of the disrupted activity of the ATP7A protein, copper is poorly distributed to cells in the body. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels.[3][4] The decreased supply of copper can reduce the activity of numerous copper-containing enzymes that are necessary for the structure and function of bone, skin, hair, blood vessels, and the nervous system.[3][5]


A proton pump inhibitor, Omeprazole, has been shown to block ATP7A, in addition to its more established role of blocking ATP4A.


  1. ^ Tümer Z, Møller LB, Horn N (1999). "Mutation spectrum of ATP7A, the gene defective in Menkes disease". Adv. Exp. Med. Biol. 448: 83–95.  
  2. ^ a b Kodama H, Murata Y (Aug 1999). "Molecular genetics and pathophysiology of Menkes disease". Pediatrics International 41 (4): 430–5.  
  3. ^ a b c d e Lutsenko S, Gupta A, Burkhead JL, Zuzel V (Aug 2008). "Cellular multitasking: the dual role of human Cu-ATPases in cofactor delivery and intracellular copper balance". Archives of Biochemistry and Biophysics 476 (1): 22–32.  
  4. ^ a b c d e Bertini I, Gray H, Stiefel E, Valentine J (2006). Biological inorganic chemistry : structure and reactivity. Sausalito, CA: University Science Books.  
  5. ^ Inesi G, Pilankatta R, Tadini-Buoninsegni F (Oct 2014). "Biochemical characterization of P-type copper ATPases". The Biochemical Journal 463 (2): 167–76.  
  6. ^ Banci L, Bertini I, Cantini F, Ciofi-Baffoni S (Aug 2010). "Cellular copper distribution: a mechanistic systems biology approach". Cellular and Molecular Life Sciences 67 (15): 2563–89.  

Further reading

  • Barnes N, Tsivkovskii R, Tsivkovskaia N, Lutsenko S (2005). "The copper-transporting ATPases, menkes and wilson disease proteins, have distinct roles in adult and developing cerebellum". J Biol Chem 280 (10): 9640–5.  
  • Greenough M, Pase L, Voskoboinik I, Petris MJ, O'Brien AW, Camakaris J (2004). "Signals regulating trafficking of Menkes (MNK; ATP7A) copper-translocating P-type ATPase in polarized MDCK cells". Am J Physiol Cell Physiol 287 (5): C1463–71.  
  • Møller LB, Tümer Z, Lund C, Petersen C, Cole T, Hanusch R, Seidel J, Jensen LR, Horn N (2000). "Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome". Am J Hum Genet 66 (4): 1211–20.  
  • Voskoboinik I, Camakaris J (2002). "Menkes copper-translocating P-type ATPase (ATP7A): biochemical and cell biology properties, and role in Menkes disease". J Bioenerg Biomembr 34 (5): 363–71.  
  • Harris ED, Reddy MC, Qian Y, Tiffany-Castiglioni E, Majumdar S, Nelson J (1999). "Multiple forms of the Menkes Cu-ATPase.". Adv. Exp. Med. Biol. 448: 39–51.  
  • Cox DW, Moore SD (2003). "Copper transporting P-type ATPases and human disease.". J. Bioenerg. Biomembr. 34 (5): 333–8.  
  • Voskoboinik I, Camakaris J (2003). "Menkes copper-translocating P-type ATPase (ATP7A): biochemical and cell biology properties, and role in Menkes disease.". J. Bioenerg. Biomembr. 34 (5): 363–71.  
  • La Fontaine S, Mercer JF (2007). "Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis.". Arch. Biochem. Biophys. 463 (2): 149–67.  
  • Lutsenko S, LeShane ES, Shinde U (2007). "Biochemical basis of regulation of human copper-transporting ATPases.". Arch. Biochem. Biophys. 463 (2): 134–48.  
  • Dierick HA, Ambrosini L, Spencer J, Glover TW, Mercer JF (1996). "Molecular structure of the Menkes disease gene (ATP7A).". Genomics 28 (3): 462–9.  
  • Tümer Z, Vural B, Tønnesen T, Chelly J, Monaco AP, Horn N (1995). "Characterization of the exon structure of the Menkes disease gene using vectorette PCR.". Genomics 26 (3): 437–42.  
  • Kaler SG, Gallo LK, Proud VK, Percy AK, Mark Y, Segal NA, Goldstein DS, Holmes CS, Gahl WA (1995). "Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus.". Nat. Genet. 8 (2): 195–202.  
  • Das S, Levinson B, Whitney S, Vulpe C, Packman S, Gitschier J (1994). "Diverse mutations in patients with Menkes disease often lead to exon skipping.". Am. J. Hum. Genet. 55 (5): 883–9.  
  • Chelly J, Tümer Z, Tønnesen T, Petterson A, Ishikawa-Brush Y, Tommerup N, Horn N, Monaco AP (1993). "Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein.". Nat. Genet. 3 (1): 14–9.  
  • Mercer JF, Livingston J, Hall B, Paynter JA, Begy C, Chandrasekharappa S, Lockhart P, Grimes A, Bhave M, Siemieniak D (1993). "Isolation of a partial candidate gene for Menkes disease by positional cloning.". Nat. Genet. 3 (1): 20–5.  
  • Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J (1993). "Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.". Nat. Genet. 3 (1): 7–13.  
  • Levinson B, Conant R, Schnur R, Das S, Packman S, Gitschier J (1997). "A repeated element in the regulatory region of the MNK gene and its deletion in a patient with occipital horn syndrome.". Hum. Mol. Genet. 5 (11): 1737–42.  
  • Yamaguchi Y, Heiny ME, Suzuki M, Gitlin JD (1997). "Biochemical characterization and intracellular localization of the Menkes disease protein.". Proc. Natl. Acad. Sci. U.S.A. 93 (24): 14030–5.  
  • Petris MJ, Mercer JF, Culvenor JG, Lockhart P, Gleeson PA, Camakaris J (1997). "Ligand-regulated transport of the Menkes copper P-type ATPase efflux pump from the Golgi apparatus to the plasma membrane: a novel mechanism of regulated trafficking.". EMBO J. 15 (22): 6084–95.  
  • Tümer Z, Lund C, Tolshave J, Vural B, Tønnesen T, Horn N (1997). "Identification of point mutations in 41 unrelated patients affected with Menkes disease.". Am. J. Hum. Genet. 60 (1): 63–71.  
  • Dierick HA, Adam AN, Escara-Wilke JF, Glover TW (1997). "Immunocytochemical localization of the Menkes copper transport protein (ATP7A) to the trans-Golgi network.". Hum. Mol. Genet. 6 (3): 409–16.  
  • Ronce N, Moizard MP, Robb L, Toutain A, Villard L, Moraine C (1997). "A C2055T transition in exon 8 of the ATP7A gene is associated with exon skipping in an occipital horn syndrome family.". Am. J. Hum. Genet. 61 (1): 233–8.  
  • Gitschier J, Moffat B, Reilly D, Wood WI, Fairbrother WJ (1998). "Solution structure of the fourth metal-binding domain from the Menkes copper-transporting ATPase.". Nat. Struct. Biol. 5 (1): 47–54.  
  • Siggs OM, Cruite JT, Du X, Rutschmann S, Masliah E, Beutler B, Oldstone MB (6 August 2012). "Disruption of copper homeostasis due to a mutation of Atp7a delays the onset of prion disease". Proceedings of the National Academy of Sciences 109 (34): 13733–13738.  

External links

  • ATP7A protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
  • GeneReviews/NCBI/NIH/UW entry on ATP7A-Related Copper Transport Disorders Includes: Menkes Disease, Occipital Horn Syndrome, ATP7A-Related Distal Motor Neuropathy
  • OMIM entries on ATP7A-Related Copper Transport Disorders
  • GeneCard
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