Copper Metabolism,ATP7AandMenkes Disease

Abstract

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.

A 37‐year‐old Menkes disease patient—Residual ATP7A activity and early copper administration as key factors in beneficial treatment

“…c. 2710C>T is predicted to convert the Pro852 residue with leucine within the actuator domain (A‐domain), which is known to be involved in dephosphorylation of the phosphatase domain (P‐domain) during catalytic cycle of ATP7A . Pro852 is conserved in all known/predicted eukaryotic copper‐binding ATPases.…”

“…2710C>T is predicted to convert the Pro852 residue with leucine within the actuator domain (A-domain), which is known to be involved in dephosphorylation of the phosphatase domain (P-domain) during catalytic cycle of ATP7A. 3 Pro852 is conserved in all known/ predicted eukaryotic copper-binding ATPases. Proline and leucine are both hydrophobic non-polar residues, but the side chain of proline forms a cyclic structure which may have a marked influence on protein architecture.…”

“…Menkes disease (MD) and occipital horn syndrome (OHS) are allelic disorders of copper metabolism leading to early neurodegeneration and connective tissue manifestations, the latter being more dominant in OHS . The defective gene ( ATP7A ) encodes a copper transporting P‐type ATPase located in the trans‐Golgi network (TGN) and delivers copper into the secretory pathway for incorporation of the metal into cuproenzymes (transport activity) . At high intracellular copper levels ATP7A traffics to the plasma membrane (PM) in small vesicles enabling removal of excess copper from the cell (trafficking activity) .…”

“…2,3 At high intracellular copper levels ATP7A traffics to the plasma membrane (PM) in small vesicles enabling removal of excess copper from the cell (trafficking activity). 3 Most of the clinical features of MD are attributable to malfunction of 1 or more important cuproenzymes, including cytochrome c oxidase, dopamine β-hydroxylase, lysyl oxidase (LOX) and tyrosinase.…”

Absorption Mechanisms of Iron, Copper, and Zinc: An Overview

“…Mutations in ATP7A gene are associated with Menkes disease, an X-linked recessive copper defi ciency disorder characterized by neurological defects, growth failure, and kinky hair (45,46). ATP7A is normally located to the trans-Golgi network, but in response to high extracellular copper, it is known to relocate to the cytosolic vesicles and undergo traffi cking to the basolateral membrane (47)(48)(49)(50). A possible mode is that ATP7A may mobilize copper into vesicles, which then fuses with the basolateral membrane to release it for export.…”