Eduardo A. Groisman knows the frustration of searching for a protein that isn't there. Ever since he was a postdoctoral fellow, Groisman, an HHMI investigator at Washington University School of Medicine in St. Louis, has been studying how Salmonella typhimurium bacteria regulate magnesium via the PhoP/PhoQ system—a two-component regulatory system that controls two of three magnesium-transporter genes. Magnesium regulation is vital for cell survival. The metal exists as a positively charged ion in biological systems, where it stabilizes DNA and RNA and is critical to certain enzymatic reactions as well as membrane and ribosome stability. In Salmonella, the PhoQ protein monitors magnesium and responds to changes in concentration by riding herd on the PhoP protein. When magnesium concentrations are low, PhoQ keeps PhoP in a form that turns on expression of the genes encoding magnesium transporters, which pump the metal ion into the cell. When magnesium is abundant, PhoQ changes PhoP into a form that shuts down expression of the three genes. "At one point, we decided to make a PhoP mutant that works independently of PhoQ," Groisman says. Presumably, genes regulated by PhoP should then be blind to the magnesium concentration. And that was true for all the genes they looked at except mgtA. This gene still turned on when magnesium was scarce and turned off when it was plentiful. Unable to identify the protein regulating mgtA, Groisman's team examined the unusually large section of the mRNA transcript preceding the sequence that actually encodes the protein. When they mutated the 5' UTR, the gene wasn't repressed in the presence of high levels of magnesium. Computational structural analysis suggested that a riboswitch may be involved in the gene's expression, and the group then proved that the 5' UTR could bind magnesium and alter the RNA's structure to halt transcription. In work published in the April 7, 2006, issue of Cell, Groisman and his colleagues announced that they had found a magnesium-binding riboswitch, the first example of a riboswitch that responds to a metal. He believes the 5' UTR of mgtA may offer some surprises—the RNA fragment can be detected in the cell after it is cleaved, indicating it may still have some unidentified function. "My fantasy," says Groisman, "is that the 5' untranslated region has a life of its own in addition to that of a riboswitch." —L.C.

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