Copper ATPases

Nitric oxide reductase (P) Nitrous oxide reductase (P) Ascorbate oxidase (P) Cytochrome oxidase (PM) Copper ATPase pumps (PM)... 

Copper absorption appears to occur through both a rapid, low-capacity system, and a slower, high-capacity system, which may be similar to the two processes seen with calcium absorption. Inactivating mutations in the gene encoding an intracellular copper ATPase have been shown to be responsible for the failure of intestinal copper absorption in Menkes disease. 

Figure 3 shows a comparison of the membrane topologies of the En. hirae CopB copper ATPase and the Ca " -ATPase of sarcoplasmic reticulum. The three-dimensional structure of the latter has recendy been derived to a resolution of 2.6 A (Toyoshima et al., 2000). The residue that has been demonstrated to be phosphorylated is the aspartic acid in the conserved sequence DKTGT (given in single-letter amino acid code. 

Studies on the mechanism of copper ATPases require highly enriched membrane preparations or purified enzyme. Naturally enriched membranes can be obtained only from specialized membrane compartments such as the sarcoplasmic reticulum or the electric organ of eels. Since copper is a toxic trace element, it is never encountered in large quantities in cells and copper ATPases are expressed at only low levels. However, the purihcation of the CopA and CopB copper ATPases of En. hirae has recently been reported (Wunderli-Ye and Solioz, in press Bissig et al., in press). Both enzymes have been shown to form acylphosphate intermediates in purihed form, reconstituted into proteoliposomes (Wunderli-Ye and Solioz, in press Wyler-Duda and Solioz, 1996). Acylphosphate formation has also been demonstrated for the human Menkes ATPase in native membrane vesicles (Solioz and Camakaris, 1997). Further mechanistic details are, however, not available. 

Figure 8 shows a scheme of the reaction cycle of copper ATPases, assuming that they work by a mechanism analogous to that of Ca - or Na+, K+-ATPases. To pump ions, the enzyme must cycle between a state with a high-affinity copper-binding site accessible from only one side of the membrane and a low-affinity state in which the copper cavity is accessible from the other side of the membrane. The high- and low-affinity forms of P-type ATPases were initially named Ei and E2 by Racker (1980) and for many years these ATPases were called E]E2-ATPases, until they were renamed P-type by Pedersen and Carafoli (1987a). 

All copper chaperones, as well as the copper-binding domains of copper ATPases characterized so far, show the typical consensus motif... 

Functional Aspects of ATP7B. Since the discovery of the Menkes and Wilson disease genes, the stndies of many research gronps revealed varions aspects of how these copper-ATPases work. The nniqne metal-binding cytosolic N-terminal domain of copper ATPases has been the focus of much research. In copper ATPases with multiple copperbinding domains, the closest to the transmembrane region appears to be frmctionally more important than the ones closest to the amino terminus. Therefore, the role of... 

---