Copper Metabolism, ATP7A and Menkes Disease


ATP7A is an ATP‐driven copper transport protein that plays an essential role in human health. ATP7A is critically involved in dietary copper uptake in the intestine. In addition, ATP7A delivers copper to numerous copper‐dependent enzymes within the secretory pathway and facilitates copper transfer to the brain. Inactivating mutations in ATP7A are associated with severe and often lethal pathologies, such as Menkes disease, occipital horn syndrome, and distal motor neuropathy. Genetic and biochemical studies have demonstrated that disease‐causing mutations disrupt ATP7A in many ways, including disruption of biosynthesis, impairment of stability, inactivation of copper transport activity and disturbance of trafficking behaviour. Cellular studies also indicate that ATP7A is a subject of complex regulation. Despite significant progress in the characterisation of ATP7A's function, cell‐specific regulation of this transporter remains poorly understood. Many aspects of pathologies caused by mutations in ATP7A require further in depth studies.

Key Concepts

  • Copper is the third most abundant trace element in the body, after iron and zinc, and it is required for normal function of important copper‐dependent enzymes. Copper deficiency is detrimental to the development and function of many organs especially the central nervous system.
  • Precise regulation of intracellular copper levels is vitally important because, although essential, excess copper has detrimental effects on metabolism. Several transporter molecules and carrier proteins are involved in regulating copper homeostasis.
  • ATP7A is a member of a large family of P‐type ATPases. These ATP‐utilising membrane proteins pump ions across cellular membranes against a concentration gradient. ATP7A is involved in the delivery of copper to cuproenzymes in the secretory pathway and in the export of surplus copper from cells.
  • Genetic defects in ATP7A leads to the X‐linked recessive Menkes disease.
  • Menkes disease is a multi‐systemic lethal disorder, marked by neurodegenerative symptoms and connective tissue manifestations.
  • Most of the clinical features of Menkes disease can be explained by deficiency of various copper‐dependent enzymes.
  • ATP7A mutations vary from single nucleotide changes to microscopically detectable chromosome abnormalities.
  • Ultimate diagnostic proof of Menkes disease is the demonstration of the molecular defect in ATP7A.
  • Menkes disease patients show progressive deterioration of brain function. Administration of copper‐histidine before brain damage may slow the disease progression and result in less severe neurological symptoms.

Keywords: ATP7A; ATP7A; copper; copper metabolism; Menkes disease; occipital horn syndrome

Figure 1. (a). Schematic illustration of cellular copper transport. Copper is taken up across the plasma membrane by the copper uptake transporter (CTR1) as cuprous ions (Cu+). Within the cytoplasm, the copper is attached to glutathione (GSH), metallothionein (MT) or copper chaperons, which deliver copper to enzymes and compartments. COX17 is the copper chaperone for cytochrome c oxidase (COX), whereas CCS is the copper chaperone for superoxide dismutase (SOD1), which resides in the cytosol or in the mitochondria. ATOX1 is the copper chaperone for ATP7A (ATP7B in hepatocytes), which is localised at TGN under basal copper levels and delivers the metal to peptidyl α‐amidating enzyme (PAM), dopamine β‐hydroxylase (DBH), tyrosinase (TYR) and the secreted enzymes LOX and extracellular superoxide dismutase (SOD3). At elevated copper concentrations, ATP7A is targeted to the plasma membrane. In the polarised cells, such as enterocytes ATP7A traffics to the basolateral surface of the cell, via small vesicular structures and facilitates delivery of dietary copper to the portal blood. TGN, trans‐Golgi network. ATP7A is indicated with green cylinders. (b). Schematic overview of copper circulation through the body. Blue arrows indicate bioavailable copper pools, whereas red arrows indicate non‐exchangeable Cu. ER, endoplasmic reticulum and TGN, trans‐Golgi network.
Figure 2. Schematic structure of ATP7A. The MBDs (light green), A‐domain (orange), N‐domain (grey) and P‐domain (blue) all are located on the cytosolic side of the membrane. The TM segments 1–8 are shown in purple. The relative positions of the PDZ motif (DTAL) and the transient phosphorylation site (DKTGT) are indicated. The aspartate which undergoes transient phosphorylation is labelled with a bold ‘D’. The N‐terminal MBDs contain characteristic copper‐binding motif CxxC, the membrane region has a CPC motif within TM6, which is essential for copper coordination and transport, and the P‐domain contains the DKTGT motif, which is invariant and includes the aspartate residue (D) critically involved in the hydrolysis of ATP.
Figure 3. The catalytic cycle of ATP7A. The catalytic cycle of ATP7A consists of four conformational states. In the E1 state, ATP7A has high affinity for Cu(I) (TM‐domain) and for ATP (A‐domain); binding of both substrates promotes ATP hydrolysis at the N‐domain/P‐domain interface (ATP‐binding pocket). Hydrolysis of ATP is accompanied with the transfer of gamma phosphate from ATP to the invariant aspartate (D1044KTGT of the P‐domain) and formation of the E1‐P state. Following formation of the transient phosphorylated intermediate, access from the cytosol to the transport site is closed and further conformational change occurs to produce the E2‐P state. Transition to the E2‐P state opens the luminal portion of the copper translocation pathway facilitating copper release. The release of copper is coupled to changes in the cytosolic domains of the protein, which lead to dephosphorylation of the transiently phosphorylated D1044. This step is facilitated by the A‐domain and causes the E2‐P state to transition to the E2 state, which closes luminal access to the intramembrane transport sites. Binding of ATP triggers the E2 to E1 transition positioning ATP7A for the next cycle. The N, A and P domains are shown in green, yellow and pink, respectively. The TM‐domain is shown in purple. Cytosolic/luminal access paths in the TM‐domain during the E1 and E2‐P states are indicated by dashed cylinders. Copper is shown as an orange ball.
Figure 4. Structure of LCopA (a). The P, N and A domains are shown in pink, green and yellow, respectively, transmembrane segments are in grey. Transmembrane domain expansion (b) shows residues of the copper entry site (green), copper‐binding sites I and II (orange and dark green, respectively) and copper release sites (pink). Image based on PDB ID: 4BBJ (Andersson et al., ).
Figure 5. (a) Clinical appearance at age 3 weeks of a patient with classical MD. Note the lax skin. (b) Scalp hair depigmented and with stubby appearance. (c) Hair microscopy (x100) of normal hair (above) and hair with pili torti (below). Reproduced with permission from Tümer Z, Møller LB () © Nature Publishing Group.


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Further Reading

Barry AN, Shinde U and Lutsenko S (2010) Structural organization of human Cu‐transport ATPases: learning from building blocks. Journal of Biological Inorganic Chemistry 15: 47–59.

Horn N and Tümer Z (2002) Menkes disease and the occipital horn syndrome. In: Royce PM and Steinmann B (eds) Connecitive Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects, 2nd edn, pp. 651–685. New York: John Wiley and Sons Inc.

Lutsenko S, LeShane ES and Shinde U (2007) Biochemical basis of regulation of human copper‐transporting ATPases. Archives of Biochemistry and Biophysics 463: 134–148.

Lutsenko S and Bhattacharjee HAL (2010) Copper handling machinery of the brain. Metallomics 2: 596–608.

Palmgren MG and Nissen P (2011) P‐Type ATPases. Annual Review of Biophysics 40: 243–266.

Tümer Z (2013) An overview and update of ATP7A mutations leading to Menkes disease and occipital horn syndrome. Human Mutation 34: 417–429.

Wu F, Wang J, Pu C, Qiao L and Jiang C (2015) Wilson's disease: a comprehensive review of the molecular mechanisms. International Journal of Molecular Sciences 3: 6419–6431.

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Pierson, Hannah, Lutsenko, Svetlana, and Tümer, Zeynep(Nov 2015) Copper Metabolism, ATP7A and Menkes Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024278]