Functions copper transport

Caeruloplasmin (Cp) is an acute phase glycoprotein with a copper transport function. At least 90% of total plasma copper is bound to Cp with the remaining 10% associated with albumin, histidine and small peptides. Lipid peroxidation requires the presence of trace amounts of transition metals and the copper-containing active site of Cp endows it with antioxidant capacity... 

ATP-dependent Ca2+ pumps and Na+,Ca2+ antiporters act in concert to maintain a low concentration of free cytosolic Ca2+ 79 The uniquely high resolution structural data available for the SERCAla Ca2+ pump illuminates the structure of all P-type transporters 81 P-type copper transporters are important for neural function 82... 

P-type copper transporters are important for neural function. Wilson s and Menke s diseases have major neurological components (Ch. 45). The Wilson s disease gene codes for a transporter, expressed chiefly in liver, that probably functions in Cu2+ excretion. The Menke s disease gene codes for a closely related transporter that regulates intestinal Cu2+ absorption [32],... 

The copper transport function of ceruloplasmin has been documented in several reviews (e.g. see refs. 15, 42, 43) and a transport function established. The turnover of ceruloplasmin allows copper ions to move from the major sites of ceruloplasmin synthesis in liver cells [44,45] to peripheral tissues for incorporation into copper-dependent enzymes [46,47], but transport mechanisms may also be active which involve copper atoms in the intact protein. However, the complexity of the protein has made it difficult to determine which, if any, of the six integral copper atoms are involved in copper delivery or whether there exist additional... 

The sequence for delivery of copper ions to SOD1 passes from the copper transporter (Ctr) by an unknown pathway to the copper chaperone for SOD1 (CCS) and by a studied pathway from CCS to SOD1. The CCS protein has been studied structurally and found to be similar to other copper chaperones such as those discussed above—Atxl and Atoxl (Hahl). Copper chaperone for superoxide dismutase (CCS) differs from other copper metallochaperones in that it folds into three functionally distinct protein domains with the N-terminal end of domain I... 

CopA of En. hirae could be expressed in Escherichia coli and purified to homogeneity by Ni-NTA affinity chromatography by means of an added histidine tag (Wunderh-Ye and Solioz, in press). Purified CopA has a pH optimum of 6.3 and a for ATP of 0.2 mM. The enzyme forms an acylphosphate intermediate, which is a hallmark of P- and CPx-type ATPases (Pedersen and Carafoh, 1987b). Purified CopA can now serve in the analysis of mechanistic aspects of copper transport and in the characterization of structure-function relationships. 

CopB was shown to catalyze ATP-driven copper(I) and sUver(I) transport into native membrane vesicles of En. hirae. Since only inside-out oriented ATPase molecules were active in this transport assay, this corresponds to copper extrusion by CopB in vivo. Copper transport by vesicles took place only under reducing conditions. Cu(I) rather than Cu(II) was thus the transported species. Use of null mutants in copA, copB, orcoj Aand copB> made it possible to attribute the observed transport to the activity of the CopB ATPase. Copper transport exhibited an apparent for Cu+ of 1 pM and a Umax of 0.07 nmol/min/mg of membrane protein. " Ag+ was transported with a similar affinity and at a similar rate (Solioz and Oder-matt, 1995). Since Cu" " and Ag+ were complexed to Tris buffer and dithiothreitol present in the assay, the values must be considered as relative only. The results obtained with membrane vesicles were further supported by evidence of " Ag+ extrusion from whole cells, preloaded with this isotope. Again, transport depended on the presence of functional... 

Considerable progress has been made toward the elucidation of the function of Cox 17 since its identification 5 years ago. It has been shown to be a copper-containing protein that is essential for assembly of the cytochrome c oxidase complex and is present in both the mitochondria and the cytosol. These features are strongly indicative of a copper chaperonelike function. It appears that Cox 17 interacts directly with Scol and Sco2, but the delineation of the remainder of the copper-trafficking pathway from the chaperone to the cytochrome c oxidase complex remains unclear. It is also unclear exactly how Cox 17 binds copper, since the CCXC motif is unique to date. If it binds three copper atoms with only three cysteine residues, the coordination of the metal ions will be extremely interesting, and elucidation of the protein structure will undoubtedly yield new insights into copper transportation in the cell. 

Payne, A. S., and Gitlin, J. D. (1998). Functional expression of the Menkes disease protein reveals common biochemical mechanisms among the copper-transporting P-type ATPases./. Biol. Chem. 273, 3765-3770. 

Metalloprotein protein that binds a specific metal ion and requires that metal ion for proper function Metal transporter transmembrane protein responsible for the translocation of metal ions across a lipid bilayer MTMl mitochondrial inner membrane transporter needed for activating SOD2 with manganese SCO Copper carrying molecule, possibly the copper chaperone or copper insertion factor for cytochrome oxidase SMF2 intracellular metal transporter essential for manganese trafficking... 

Copper The daily intake from food is 0.8—2.0 mg it is released into the portal vein via copper-transporting ATPase. The transport of copper, which is toxic in its free form, is effected by the binding to ceruloplasmin, albumin and transcuprin. Copper is bound to reduced glutathione and metallothionein in the hepatocytes and distributed to various organelles or incorporated into enzymes. The biological effects of copper are manifold and essential for some cellular functions, (s. p. 50) Copper is toxic not only in its free form, but also in cases of overload (e. g. cirrhosis in childhood due to the consumption of water from copper pipes). Copper homoe-ostasis is regulated via biliary excretion (normal value about 1.2-2.0 mg/day), so that the normal value in serum is 75-130 fg/dl. (321, 323, 370, 383, 386) (s. p. 102)... 

The high-affinity pathway involves oxidation of Fe to Fe by the ferroxidase FET3 and subsequent transport of Fe " " across the plasma membrane by the permease FTRl. FET3p is a member of the family of multicopper oxidases, which include ascorbate oxidase, laccase, and ceruloplasmin (see Chapter 14), and does not become functional until it is loaded with copper intracellularly through the activities of the copper chaperone ATX Ip and the copper transporter CCC2p. It appears that Fe " " produced by FET3 is transferred directly to FTRl, and does not equilibrate with the bulk phase, as is illustrated in Fig. 7.13. This is almost certainly achieved by the classic metabolite-channeling mechanism, a common feature of multifunctional enzymes. 

The brain barrier systems, i.e., the blood—brain and blood—cerebrospinal fluid barriers, ensure that there are adequate supplies of zinc, copper, and iron available for brain function and prevention of neurological diseases. Too much or too little will be detrimental to brain function. Specific transporters present on the BBB will ensure the passage of each of these metals across this barrier. 

Kuo, Y. M., Zhou, B., Cosco, D., Gitschier, J. (2001). The copper transporter Ctrl provides an essential function in mammalian embryonic development. Proceedings of the National Academy of Sciences of the United States of America, 98, 220—225. 

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