Diverse cellular and developmental processes are controlled by reversible phosphorylation – the process by which phosphates are added or removed from proteins. Reversible protein phosphorylation is widely used in biological systems to control the activity of enzymes or the association of proteins with other proteins. Kinases and phosphatases control the phosphorylation state of target proteins in response to specific cellular or environmental cues, meaning that kinases and phosphatases must themselves be highly regulated to be active at the right place and at the right time. A widespread family of phosphatases called PP2C, which is found in bacteria, plants and animals, was known to be highly regulated, but the mechanism by which phosphatase activity is controlled was unknown.
In a collaboration between the Losick and Gaudet laboratories and the Wilkinson group in York England, Niels Bradshaw and coworkers asked how the activity of one PP2C phosphatase is regulated, reasoning that the answer would reveal general principles of how other members of the family are regulated. One of the best ways to understand how a protein is regulated is to determine its structure in the active and inactive states. They hoped that a comparison of the two structures would reveal a feature that explains how phosphatase activity is regulated and that this feature would be common to other members of the family
By determining the structure of a bacterial phosphatase in active and inactive states, Bradshaw and coworkers discovered a structural element that acts as a switch to control its activity. Movement of this switch is coupled to recruitment of metal ions needed for the phosphatase to be active. Gratifyingly, they found that the switch is broadly shared by members of the family. Beyond their expectations, they discovered that a seemingly unrelated family of enzymes has a similar architecture and is controlled by a similar switch. This other family is called proteasomal proteases and is responsible for degrading other proteins. Thus, the phosphatase and protease families may have a common evolutionary history. A new concept from our work is that regulatory mechanisms may be important for driving the evolution of new protein functions.
Multiple members of the PP2C family are involved in cancer and other diseases. The discovery of a conserved regulatory switch provides new opportunities to pharmacologically control phosphatase activity in a therapeutic context. Many cancer drugs that are currently in use or are in development target protein kinases, but efforts to target protein phosphatases have largely been unsuccessful. The discovery of the PP2C regulatory switch may enable the development of molecules that target protein phosphatases.
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by Niels Bradshaw and Rich Losick
