Research Notes

Aided by the brilliant X-rays produced by synchrotron radiation at the Argonne National Laboratory in Illinois, a group of scientists from Northwestern University have determined the complete molecular structure of the copper chaperone for superoxide dismutase (CCS) ("Heterodimeric structure of superoxide dismutase in complex with its metallochaperone," Nature Structural Biology, 8[9]:51-5, Sept. 2001). The metallochaperone's structure was known except for the third domain. Now, researchers suspect, through genetic evidence and structure, that this armlike structure is responsible for delivering copper to its target protein, zinc superoxide dismutase (SOD1). When CCS docks with SOD1, the arm becomes more ordered in its interaction. By using X-rays that are many magnitudes brighter than normal, this domain could be clearly viewed. Synchrotron radiation is 10 orders of magnitude, or 10 billion times more brilliant, than the standard laboratory X-ray source. According to Amy Rosenzweig, assistant professor of biochemistry, molecular biology, and cell biology of chemistry, "This discovery is significant because it's the first structure of a metallochaperone-target protein complex. This shows a molecular picture of how the metal transfer may take place between a chaperone and its target protein." CCS is a unique chaperone because it's structurally similar to its target protein. CCS, normally found in the cell as a homodimer, breaks apart, with one copy linking up with a copy of SOD1, not unlike a handshake. At this point, researchers think the "arm" comes down and delivers the copper to SOD1. Rosenzweig says that this mechanism might be used by other chaperones as well. --Hal Cohen Simple Solution for Hearing Loss? In the Republic of Georgia, tuberculosis is still a relatively common disease. Doctors typically prescribe the least expensive and most commonly available drugs: aminoglycosides such as streptomycin or kanamycin. Aminoglycosides often eliminate the tuberculosis bacteria, but they also often cause mild to profound hearing loss. In a visit this summer to the Center for Hearing Rehabilitation in Tblisi, Jochen Schacht, scientific director of the Kresge Hearing Research Institute at the University of Michigan, discussed a possible intervention derived from ongoing research in his laboratory. Schacht's lab has discovered that the mechanism for hearing loss from gentamycin and other aminoglycoside antibiotics is due to free-radical formation. Schacht induced profound hearing loss in mice and guinea pigs by injecting aminoglycosides, and then applied a cotreatment with antioxidants. (S.H. Sha et al., "Antioxidants attenuate gentamycin-induced free radical formation in vitro and ototoxicity in vivo: D-methionine is a potential protectant," Hearing Research, 142:34-40, 2000.) "The antioxidants prevented hearing loss from occurring almost completely," he says. The simplest salycilate compound, essentially the active component of aspirin, could prevent hearing loss. This finding was especially promising because aspirin is inexpensive. Currently, Schacht and his Georgia colleagues are planning a clinical investigation for tuberculosis patients taking gentamycin. Patients would take streptomycin and aspirin concurrently. In studying noise-induced hearing loss, Schacht also found a build-up of free radicals leads to hearing loss. Although a similar treatment with antioxidants might be protective, people with noise-induced hearing loss usually seek treatment after the damage has already occurred. --Jennifer Fisher Wilson Crystal Structure of aVb3 Researchers at Massachusetts General Hospital (MGH) have solved the structure of integrin aVb3 after they fully determined its extracellular portion (J.-P. Xiong et al., "Crystal structure of the extracellular segment of integrin aVb3," Science Express, www.sciencemag.org/cgi/content/abstract/1064535, Sept. 6, 2001.] The receptor's structure was determined once researchers obtained the protein's purified form, crystallized it, and then gathered its reflections using X-ray crystallography. Program director M. Amin Arnaout says that many factors made crystallization difficult. "A highly glycosolyated protein is hard to get into a crystal structure because it doesn't pack together as tightly. We also had to remove the transmembrane segments without affecting its functionality and make sure that the heterodimer didn't separate. ... We tried well over 1,000 different conditions before we were able to crystallize it." Like classic receptors, integrin receptors are promiscuous in nature and can bind to a variety of ligands. However, integrin receptors undergo shape-shifting when they become activated. Viral proteins, similar in structure to the proteins called for by the cell, can hijack these receptors to gain entrance to the cell. This receptor, which is associated with diseases such as osteoporosis, will have drug designers looking to target the ligand-binding site to fight these maladies. With 24 integrin receptors controlling almost every kind of cell process, Arnaout feels the discovery's greatest implication is that it will help to determine the remaining structures. "When you know one of them, you can do some modeling for the others." --Hal Cohen

Research Notes

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