Kinases call a lot of the shots inside cells. These essential enzymes regulate a vast array of processes, such as whether cells grow normally or become cancers. But the functions of many of the over 120 kinases that exist in yeast are mysteries—and no simple method exists to determine each one's modus operandi. Now, chemical and genetic engineering has allowed a team of researchers at the University of California, San Francisco, led by HHMI investigators Erin K. O'Shea (now at Harvard University) and Kevan M. Shokat, to pinpoint the protein substrates acted on by a yeast kinase called Pho85. "To understand the function of a particular kinase, we need to know what kinds of proteins it controls," says O'Shea.

The researchers expect their two-step method will prove useful for many kinases, especially because no one else has come up with a systematic approach to identifying a kinase's constellation of substrates.

Kinases activate proteins by grabbing the cellular energy-supplying molecule ATP (adenosine triphosphate), shearing off a phosphate, and adding it to the protein. Using radioactive ATP as a source of phosphate is one way to mark targeted proteins so that they can be identified amid a sea of others. But all 120 kinases exist in test tube extracts of yeast, and each of those can affix radioactive phosphate to proteins.

Illustration: Joel Lardner

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