Londergan Lab Receives Major Grant
Assistant Professor of Chemistry Casey H. Londergan has been awarded a $303,153 grant from the National Institute of General Medical Sciences (NIGMS). The award is a competitive renewal of a previous grant from the agency, which is the basic science arm of the National Institutes of Health, and will support Londergan's continued research on the structures of proteins.
Londergan's lab has developed a way to use an artificial amino acid (one that does not occur naturally in proteins) to provide an optical signal that depends on the dynamic structure around a specific, chosen site in proteins. That artificial amino acid, known as "cyanylated cysteine," is then placed in proteins through a process that uses molecular biology (to alter the protein's amino acid sequence) and then chemistry (to incorporate the artificial amino acid).
“Our research generally tries to develop and apply new ways to characterize the structures of proteins that are very floppy or dynamic,” Londergan says. “Many of these proteins are involved in signaling and regulation inside cells, but how they do their jobs is not well-understood because there is no good picture or description of their evolving and flexible shapes. Our approach is unique in that it combines molecular biology, chemistry, and infrared spectroscopy to provide a new set of eyes on a small, chosen piece of what can be a very large and complicated protein.”
The NIGMS grant will support research on two different proteins, which, if understood better, could have a variety of potential future applications.
The first protein is from a class of viruses called paramyxoviruses, which includes measles and mumps and some other newer and more deadly viruses like the Hendra and Nipah viruses. “Our goal here is to use our methodology to fully characterize the flexible bound structures that this protein can adopt, with the eventual outcome of finding a way to prevent that binding process and thus disable the virus's ability to replicate itself,” says Londergan, who has been collaborating for the past several years with Professor Sonia Longhi of CNRS-Marseille in France, an international expert in virology and disordered protein structure.
A number of Haverford students have been centrally involved in this project, including David Snead '08, Connor Bischak '10 and Hailiu Yang '11. Going forward, the NIGMS funding will enable students to work in Longhi's laboratory during the summer to make new modified proteins that they will bring back to Haverford for chemical modification and vibrational spectroscopy experiments. The first to go will be Sara Hess '13, who will spend the summer of 2012 in Marseille in Dr. Longhi's laboratory making samples for her senior thesis work.
The second protein the lab is studying is calmodulin, a protein that changes shape when it senses the release of calcium. “A better understanding of calmodulin's bound structures would lead to a much better picture of how calcium signaling works and possibly point the way to new ways to manipulate cells that have become misregulated in disease states,” Londergan says.“This could be important to problems as wide-reaching as cancer, neurodegenerative disease, and other organ dysfunction disorders.”
The Londergan lab's work with calmodulin was facilitated by collaboration with Haverford Chemistry Professor Karin Akerfeld and Professor Sara Linse of Lund University in Sweden. “My former postdoc Shannon Dalton, who got her Ph.D. at Bryn Mawr, and a group of talented Haverford students including Sara Hess '13, Kanika Ramchandani '14 and Ishita Dhawan '14 helped to get this project off the ground last year,” says Londergan.“And we are looking forward to involving many more students in the next two years as we create new optically-active variants of calmodulin at Haverford.”