Research

In a rapidly changing world, cells must sense changes in their environment and quickly respond in order to survive. So how does the inside of the cell know what is going on outside of its membrane? A common strategy is to have a protein across the membrane that can sense the differences on either side. The importance of this type of membrane spanning protein is reflected in that they represent ~50-70% of all pharmacological therapeutic targets. Therefore, we believe it is of great importance to understand the mechanism of how a cell senses and responds to a changing environment, which requires a detailed, atomic-level description of the proteins involved in this process. We use x-ray crystallography as the primary tool to determine these atomic-level descriptions of these proteins that respond to a dynamic environment.

One example of how a cell responds to an environmental change is the change in metabolism during a switch from an aerobic environment to an anaerobic environment. E. coli responds to this challenge by changing its respiratory chain constituents. One of the necessary changes in this process is the substitution of the integral-membrane complex II for a closely related homolog. During aerobic respiration, this protein, succinate:quinone oxidoreductase, catalyzes the oxidation of succinate to fumarate. As the cell’s environment becomes anoxic, the homolog quinol:fumarate reductase preferentially catalyzes the reverse reaction, that is the reduction of fumarate to succinate. Each protein is specific for the direction of the reaction, despite having an extremely similar sequence. We have laid the ground work for understanding how the quinol:fumarate reductase functions in the anaerobic respiratory process and are further investigating how it catalyzes a chemical reaction preferentially in one direction or the other.

Eukaryotic cells have evolved sophisticated mechanism to determine if a stimulus is present so that they may appropriately respond. Their signaling recycles the architecture of the proteins involved, but they react with extreme specificity nonetheless. One method requires signaling by G-proteins. The conformational changes in the G-proteins are critical for transducing information about how a cell should act in response to its current situation. We are investigating these how the protein alters its conformation to understand how eukaryotic systems sense and respond to the changes in their environment.