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The copper-transporting ATPase ATP7B (Wilson ATPase) is a large trans-membrane protein with a complex multidomain architecture. ATP7B uses the subset of these domains to hydrolyze adenosine triphosphate (ATP) and to couple ATP hydrolysis with the transport of copper across the cell membranes. These activities are central to main physiological functions of ATP7B: the maintenance of copper homeostasis and synthesis of active ceruloplasmin. The other domains of ATP7B are used for regulation: using these structural elements, ATP7B responds to changing copper concentration in the cytoplasm and other signaling events. In this review, we summarize the available structural information on ATP7B and relate, whenever possible, the structural features of ATP7B to its function and regulation.

Wilson disease (WD) is caused by mutations in the ATP-dependent copper transporter ATP7B. Over 500 WD mutations have been identified, and frequencies of most common mutations have been established for different populations. Over the years, significant progress has been made in predicting consequences of various substitutions and testing these predictions experimentally. In this chapter, we focus on biochemical and cellular effects of representative WD-causing mutations and summarize available data for the best characterized variants. We highlight a spectrum of consequences of WD mutations, which range from the complete loss of structural integrity or transport function to a disruption of some aspects of ATP7B behavior without significant change in the others. The emerging role of single nucleotide polymorphisms as factors modifying properties of ATP7B is also discussed.

Cu-transporting ATPases or Cu pumps are essential for normal homeostasis of all living organisms. Their activity is required for microbial pathogenicity, pheromone sensing by plants, neuronal activity in mammals, and many other physiological processes. Cu pumps transport copper from the cytosol across membranes to maintain copper balance and deliver copper cofactor to cuproenzymes. Genetic mutations in human Cu pumps result in severe disorders, Menkes disease, and Wilson's disease. This article describes the biological roles of Cu pumps, discusses the structure and mechanism of Cu pumps in comparison to other P-type ATPases, and summarizes the current data on Cu pump regulation.