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When errant proteins stray, a cellular cowboy rides in to save the day

In the drama of life at the cellular level, proteins can be heroes or villains. When they’re wearing their white hats, proteins provide and maintain structure, act as enzymes and hormones and perform vital functions such as transporting oxygen in the blood. But they can also run amok, contributing to cancer, heart disease and inflammatory conditions such as rheumatoid arthritis.

The cellular scenario of this Wild West tale stars Protac, a molecule developed by researchers at Yale and Howard Hughes Medical Institute investigators at the California Institute of Technology. Playing the role of the sheriff galloping in to save the day, Protac rounds up rogue proteins inside cells and orchestrates the proteins’ demise. One end of the dumbbell-shaped molecule is customized to bind to the protein of interest; the other end homes in on the cell’s natural protein-degrading apparatus. “By bringing the protein into close proximity to the degradation machinery, you can target it for destruction,” said Craig M. Crews, Ph.D., an associate professor in the Department of Molecular, Cellular, and Developmental Biology with joint appointments in chemistry and pharmacology.

In a presentation at the Experimental Biology 2003 meeting in San Diego in April, Crews and co-workers showed that Protac—for protein-targeting chimera—degrades targeted proteins in intact cells. In a proof-of-concept experiment, they engineered Protac to bind to green fluorescent protein (GFP), a naturally occurring protein that gives off a bright, green glow under ultraviolet light. When Protac was added to cultured cells containing GFP, it gathered up the glowing protein and promoted its destruction. Within an hour, the cells that contained GFP had lost their fluorescence.

While Protac has potential for treating disease, its more immediate use probably will be in screening large numbers of proteins for better understanding of their functions, much as genetic screens currently are used, said Crews.

“When a genetic screen is used to study some aspect of cell biology, the process involves generating a lot of different mutants that are each defective in some gene that encodes some protein, and then looking for individuals that have a defect in the particular process that you’re interested in. The geneticist then determines which gene, and which corresponding protein function, has been altered,” said Crews. “But there are several areas of cell biology that are difficult to study using traditional genetics. So what we’d like to do is induce the loss of protein function, not by altering the underlying encoding mechanism—the DNA—but by physically inducing the degradation of particular proteins. One can imagine doing large-scale screens, knocking out every protein individually and looking for loss of particular functions. In this way, we hope to discover new, critical proteins that are required for intracellular processes. So in addition to targeting known proteins, we hope this molecule will aid in the discovery of things we don’t even know about.”