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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

Wilson's disease (WD) is a human disorder of copper homeostasis caused by mutations in the copper-transporting ATPase ATP7B. WD is characterized by copper accumulation, predominantly in the liver and brain, hepatic pathology, and wide differences between patients in the age of onset and the spectrum of symptoms. Several factors contribute to the phenotypic variability of WD. The WD-causing mutations produce a wide range of changes in stability, activity, intracellular localization, and trafficking of ATP7B; the nonpathogenic genetic polymorphisms may contribute to the phenotype. In Atp7b(-/-) mice, a mouse model of WD, an abnormal intracellular distribution of copper in the liver triggers distinct changes in the transcriptome; these mRNA profiles might be used to more specifically define disease progression. The major effect of accumulating copper on lipid metabolism and especially cholesterol homeostasis in mice and humans suggests the importance of fat and cholesterol metabolism as modifying factors in WD.

Human Cu-ATPases ATP7A and ATP7B maintain copper homeostasis through regulated trafficking between intracellular compartments. Inactivation of these transporters causes Menkes disease and Wilson disease, respectively. In Menkes disease, copper accumulates in kidneys and causes tubular damage, indicating that the renal ATP7B does not compensate for the loss of ATP7A function. We show that this is likely due to a kidney-specific regulation of ATP7B. Unlike ATP7A (or hepatic ATP7B) which traffics from the TGN to export copper, renal ATP7B does not traffic and therefore is unlikely to mediate copper export. The lack of ATP7B trafficking is not on account of the loss of a kinase-mediated phosphorylation or simultaneous presence of ATP7A in renal cells. Rather, the renal ATP7B appears 2-3 kDa smaller than hepatic ATP7B. Recombinant ATP7B expressed in renal cells is similar to hepatic protein in size and trafficking. The analysis of ATP7B mRNA revealed a complex behavior of exon 1 upon amplification, suggesting that it could be inefficiently translated. Recombinant ATP7B lacking exon 1 traffics differently in renal and hepatic cells, but does not fully recapitulate the endogenous phenotype. We discuss factors that may contribute to cell-specific behavior of ATP7B and propose a role for renal ATP7B in intracellular copper storage.

Wilson's disease protein (WNDP) is a copper-transporting P(1)-type ATPase which plays a key role in normal distribution of copper in a number of tissues, particularly in the liver and the brain. Copper has numerous effects on WNDP, altering its structure, activity, and intracellular localization. To better understand the function of this copper-transporting ATPase and its regulation by copper, we have recently developed the functional expression systems for WNDP and for Atox1, a cytosolic protein that serves as an intracellular donor of copper for WNDP. Here we summarize the results of our experiments on characterization of the enzymatic properties of WNDP and the effects of Atox1 on the WNDP activity.

Copper is an essential element for human growth and development. Abnormal copper metabolism is associated with severe and potentially lethal disorders. Previous studies of copper misbalance in the ...