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Meet the Community: Rachelle Gaudet
By Peter Farley
By night, there's a good chance you'll find MCB Assistant Professor Rachelle Gaudet, Ph.D., burning up Boston-area dance floors doing the Lindy Hop, an exuberant swing dance born in the raucous ballrooms of 1920s Harlem. Gaudet keeps some pretty hot stuff on hand in the lab as well: in one line of her research, she uses capsaicin, the fiery compound found in chili peppers, in a form so pure it's 80 times more blistering than the hottest habanero. Gaudet uses X-ray crystallography to study the structure of TRP (pronounced "trip") channels, a unique family of ion channels that can be activated either by chemicals like capsaicin or by specific temperature ranges. When we eat spicy foods, capsaicin molecules bind to TRPV1 channels in receptor cells in our tongue, and the channels open to admit calcium into the cell; however, these same channels also open if we eat food warmed to about 42 degrees Celsius. TRPM8, on the other hand, responds to either menthol or cool temperatures. Activated TRP channels cause receptor cells to send identical messages to the brain whether they are triggered by chemicals or temperature, so we perceive menthol breath mints as "cool" and curries as "hot." The quirkiness of TRP channels would be enough to make them ripe for study, but they have also attracted intense scientific interest because the TRP family is profusely expressed in the body's pain receptors. If we understand the detailed molecular structure of these channels, Gaudet says, it may be possible to create a new class of painkilling drugs. In a strategy she calls "divide and conquer," Gaudet and her students are using bioinformatics techniques to break down the large, membrane-spanning TRP proteins into more manageable units. For example, by focusing on just the cytosolic domain of TRPV1, the team is studying whether this region binds to calmodulin, which desensitizes the channel and regulates the influx of calcium into the cell.
Gaudet's other major research effort, begun as an MCB postdoc, focuses on a transporter protein known as TAP, which is essential to an immune system process known as antigen presentation. In every nucleated cell in the body, proteins that have outlived their usefulness are targeted for destruction. The proteasome does constant cleanup duty by cleaving these proteins into short chains of amino acids that migrate through the cytosol to the endoplasmic reticulum (ER). These peptides are transported across the ER membrane by TAP and loaded onto MHC I molecules, which then travel back to the cell surface to "present" the peptides for inspection by the immune system's T cells. "The end result is that there's a constant sampling of what proteins are being synthesized within the cell," Gaudet says. "That's the way the immune system keeps track of whether cells are still behaving normally." If all goes well, when an MHC I molecule presents a foreign string of protein, such as those synthesized by a virus, T cells will move in for the kill. Using crystallographic techniques, Gaudet recently determined the structure of TAP1, one of two cytosolic domains where TAP binds peptides before transporting them across the ER membrane. TAP is just one of a group of transporters, known as ABC transporters, that bind ATP to gain enough energy to move material across membranes. Gaudet's group recently identified a sequence in both TAP subunits that appears to be absent in other ABC transporters. In a series of in vitro studies, the Gaudet group showed that deleting this sequence did not prevent TAP from transporting peptides or loading them onto MHC I molecules, but the transporter did its job much less efficiently. Gaudet predicts that the TAP-specific sequence discovered in her lab will be found to bind to a protein called tapasin, an adapter molecule that tightly links MHC I molecules to TAP. "We like this result," she says. "Since tapasin is an adapter molecule that is specific to this peptide-transport system, as opposed to other ABC transporters, it makes sense that this sequence is only present in TAP." Gaudet's lab now includes an undergraduate, a graduate student, two postdocs, and two technicians. She says that despite MCB's relatively small size, the diversity and quality of research in the department make for an unusually supportive and fertile atmosphere for doing science. "Within a fairly small department, there's a very broad spectrum of research–not only different biological systems, but different approaches that range from whole-animal studies to the chemical studies that we structural biologists do," she says. "But every laboratory has not just different research, but research that's on the edge of what's going on in their respective fields. It's pretty exciting to be around."
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