Copper transport proteins

Dancis, A., Yuan, D. S., Haile, D., Askwith, C., Eide, D., Moehle, C., Kaplan, /., and Klausner, R. D. (1994). Molecular characterization of a copper transport protein in S. cerevisiae An unexpected role for copper in iron transport. Cell 76, 393-402. 

Ceruloplasmin, a protein from the a-globulin fraction of human plasma, is usually considered to be the major copper transport protein. However, it also catalyzes the oxidation of biogenic amines, including catecholamines, adrenaline, noradrenaline, dopamine, and the indoleamine 5-hydroxytrypta-mine (5HT). 

Crider, S.E., Holbrook, R.J., Franz, K.J. Coordination of platinum therapeutic agents to met-rich motifs of human copper transport protein. Metallomics 2, 74—83 (2010)... 

Severe alterations in copper metabolism occur in two genetic disorders, Wilson s disease and Menkes disease, both of these diseases arc rare and occur in about one in 100,000 birtKs. Both diseases involve naturally occurring mutations in copper transport proteins, i.e membrane-bound proteins that mediate the passage of copper ions through cell membranes. The copper transporters that are defective in these two diseases are not the same protein, but they are related. To express this relation in numbers, over half (57 a) of the sequence of amino adds, as they occur in the polypeptide chains, are identical. Both proteins are thought to utilize ATP to drive copper ions through membranes. 

The defect in Wilson s disease has been traced to a mutation in a copper transport protein. For clarity and brevity, the term "VSfiIson s proteirt" may be used to refer to normal and mutated versions of this copper transport protein. Mutations in the Wilson s protein result in a defect in the normal passage and elimination of copper from the liver cell via the bile. Another defect is the failure to load copper ions into ceruloplasmin. The most common occurring mutation in the gene coding for Wilson s protein results in a change of His 1069 to Gin 1069 (Shah et ai., 1997). The numbers refer to the sequence of amino acids in the polypeptide chain. 

Cp may transport small amounts of copper to tissue, which have separate membrane receptors for Cp- and albumin-bound copper. The importance of Cp in transport is debated, however, because turnover of Cp copper is very slow and individuals with genetic deficiency of Cp have no problems related to copper transport (see later in this chapter). Albumin and transcuprein are the major copper transport proteins, especially following absorption from the intestinal tract. 

In another rare inherited disorder, called Wilson s disease, excessive amounts of copper accumulate in liver and brain tissue. A prominent symptom of the disease is the deposition of copper in greenish-brown layers surrounding the cornea, called Kayser-Fleischer rings. Wilson s disease is now known to be caused by a defective ATP-dependent protein that transports copper across cell membranes. Apparently, the copper transport protein is required to incorporate copper into ceruloplasmin and to excrete excess copper. In addition to a low copper diet, Wilson s disease is treated with zinc sulfate and the chelating agent penicillamine (p. 123). Describe how these treatments work. (Hint Metallothionein has a greater affinity for copper than for zinc.)... 

For a long time erythrocuprein was thought to act exclusively as a copper-transporting protein. This was a very attractive conclusion since over 50% of the erythrocyte copper content is present in erythrocuprein (60). However, in the absence of any known function of a metalloprotein, it is always tempting to assign to it the role of storage or transport of the respective metal ions. For example, caeruloplasmin was considered to be the main copper-transporting protein in blood plasma. It subsequently turned out that this copper protein is a key enzyme in iron metabolism, responsible for the oxidation of Fe2+ to the Fe3+ bound in transferrin (130—132). 

Hepatolenticular degeneration, Wilson s disease, is a severe heritable disorder of copper metabolism. The defect is caused by diminished synthesis of the copper-transporting protein ceruloplasmin and impaired excretion of copper into the bile. Copper concentration is extremely low in blood serum and high in urine furthermore, copper accumulates in liver, brain, kidney, and cornea. Chelating therapy with D-penicillamine is the medication of choice [48]. To improve copper metabolism, zinc therapy is also used [50]. 

Ligands by themselves are often effective drugs or detoxificants. For example, D-penicil-lamine (3, a substituted cysteine) is used to mobilize copper deposited in reducing tissues in patients with Wilson s disease (hepatolenticular degeneration), a hereditary defect in copper metabolism. The copper transport protein (ceruloplasmin) of blood plasma is faulty and bonds copper ions less effectively than it should. The enantiomeric L-penicillamine is ineffective as a treatment. If (as may happen) D-penicillamine is either inactive or gives rise to intense nausea, triethylenetetraamine (trien 4) is often used. 

Banci L, Bertini I, Mangani J (2005) Integration of XAS and NMR techniques for the structirre determination of metallojnotems. Examples from the smdy of copper transport proteins. Synchrotron Radiat 12 94—97... 

An essential trace element for which there is a daily requirement of 2.5 mg. A normal adult contains about 100 mg. In plasma, most copper is carried by a specific copper transport protein, caeruloplasmin. Copper is also found in certain copper storage proteins erythrocuprein (in erythrocytes), cerebrocuprein (in the brain) and hepatocuprein (in the liver). 

Frieden, E, and Hsieh, H, S. (1976) Ceruloplasmin The copper transport protein with essential oxidase activity, in "Advances in Enzymology and Related Areas of Molecular Biology". 

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