Heavy metal ions, which are toxic to cells, are nevertheless required in tiny amounts in a few key components of the cell's biochemical machinery. A team of scientists has now shown that a special "chaperone" protein encases one of these hazardous materials, copper, to safely escort it through the interior of the cell and deliver it to the specific site where it is needed. The existence of the copper chaperone suggests that other essential metals, such as zinc and iron, may have their own chaperones that function similarly.
The finding is reported in the Oct. 31 issue of the journal Science and is discussed in an accompanying editorial.
Researchers at Northwestern University, Johns Hopkins University and the University of Michigan showed that the copper chaperone protein, which floats freely inside the cell, picks up copper in its most highly reactive chemical state from a "pump" protein that is embedded in the cell's wall. The chaperone then transports this important but dangerous cargo to a few enzymes that use it to catalyze vital biochemical reactions.
"The cell needs copper and a few other heavy metals for essential enzymes, but when they're not in an enzyme's active site they can destroy cellular components," said Thomas O'Halloran, professor of chemistry at Northwestern and one of three senior authors on the paper.
The human body contains only five thousandths of an ounce of copper; a penny (which is actually 97.5 percent zinc) weighs 17 times as much.
The copper chaperone provides clues to the toxic mechanisms of other metals, such as silver and mercury, and also to two rare fatal diseases of copper metabolism, Wilson disease and Menkes' disease. These hereditary diseases each occur roughly once in every 30,000 births.
The researchers studied the copper chaperone protein from yeast, which provides a good model of copper metabolism in animal cells. They cloned the gene and put it into bacteria, which made large quantities of the protein for physical study. The human copper chaperones (there are known to be more than one) are required to transport copper, but diseases related to their malfunction have not yet been identified. The protein that malfunctions in Wilson and Menkes' diseases normally receives copper from a copper chaperone and has a very similar design to it, O'Halloran said.
Wilson and Menkes' diseases are not probably not the only disorders of copper metabolism. Another protein very similar to the copper chaperone is believed to carry copper to an enzyme called superoxide dismutase, or SOD, a primary antioxidant in the cell. Some researchers think that disorders in copper metabolism or in SOD itself play a role in the neurodegenerative disease ALS, or Lou Gehrig's disease.
Studying the function of the copper chaperone also should help scientists understand how other toxic metals are handled within the cell, O'Halloran said. "Mercury and silver are not essential to yeast or humans and therefore not likely to have chaperones," O'Halloran said. "But they might piggyback on the other metals' chaperones and wreak havoc on the cell."
Geneticist Valeria Culotta and her co-workers at Johns Hopkins SuJu Lin and Paul Schmidt cloned the copper chaperone protein gene in yeast and proved that the chaperone actually touches the protein to which it transfers the copper.
Spectroscopist James Penner-Hahn of the University of Michigan and his student Katrina Peariso used synchrotron radiation to probe the chemical state of copper within the chaperone protein. Robert Pufahl, Chris Singer and Christoph Fahrni worked with O'Halloran at Northwestern to isolate and characterize the chaperone protein molecule itself.
The research was supported by the National Institutes of Health.