title: Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis.
abstract: Copper is essential for human health and copper imbalance is a key factor in the aetiology and pathology of several neurodegenerative diseases. The copper-transporting P-type ATPases, ATP7A and ATP7B are key molecules required for the regulation and maintenance of mammalian copper homeostasis. Their absence or malfunction leads to the genetically inherited disorders, Menkes and Wilson diseases, respectively. These proteins have a dual role in cells, namely to provide copper to essential cuproenzymes and to mediate the excretion of excess intracellular copper. A unique feature of ATP7A and ATP7B that is integral to these functions is their ability to sense and respond to intracellular copper levels, the latter manifested through their copper-regulated trafficking from the transGolgi network to the appropriate cellular membrane domain (basolateral or apical, respectively) to eliminate excess copper from the cell. Research over the last decade has yielded significant insight into the enzymatic properties and cell biology of the copper-ATPases. With recent advances in elucidating their localization and trafficking in human and animal tissues in response to physiological stimuli, we are progressing rapidly towards an integrated understanding of their physiological significance at the level of the whole animal. This knowledge in turn is helping to clarify the biochemical and cellular basis not only for the phenotypes conferred by individual Menkes and Wilson disease patient mutations, but also for the clinical variability of phenotypes associated with each of these diseases. Importantly, this information is also providing a rational basis for the applicability and appropriateness of certain diagnostic markers and therapeutic regimes. This overview will provide an update on the current state of our understanding of the localization and trafficking properties of the copper-ATPases in cells and tissues, the molecular signals and posttranslational interactions that govern their trafficking activities, and the cellular basis for the clinical phenotypes associated with disease-causing mutations.
authors.affiliation: Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, 221 Burwood Highway, Burwood, Vic. 3125, Australia. sharonl@deakin.edu.au
authors.forename: Sharon
authors.initials: S
authors.lastname: La Fontaine
authors.forename: Julian F B
authors.initials: JF
authors.lastname: Mercer
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D006527:Hepatolenticular Degeneration / Q000175:diagnosis / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D007706:Menkes Kinky Hair Syndrome / Q000175:diagnosis / Q000235:genetics; D009154:Mutation; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals; D021381:Protein Transport
chemical_list: D027682:Cation Transport Proteins; D021382:Protein Sorting Signals; D003300:Copper; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; C000612464:ATP7B protein, human; D000073840:Copper-Transporting ATPases