The extraordinary diversity of protein structures and activities provides much of the molecular basis for life. I am interested in gaining a new understanding of protein structure and mechanism by utilizing a combination of structural methods and biochemistry. My lab’s current projects focus on folic acid-dependent enzymes and their interactions with other proteins. In humans, the enzymes in the folic acid pathway are associated with a number of diseases, including cardiovascular disease, stroke, neural tube defects (e.g., spina bifida) and mental illnesses. Our primary targets of study are two different enzymes that both catalyze the formation of the amino acid methionine.
Current projects include 1) Determining the three-dimensional structures of cobalamin-dependent methionine synthase, a protein that makes very large movements during catalysis, in each of the protein’s major catalytic conformations. We do this by introducing genetic mutations that favor a single conformational state and imaging the resultant proteins in a transmission electron microscope. The two-dimensional images are analyzed computationally to determine three-dimensional structures. 2) Investigating the interaction of the cobalamin-independent methionine synthase with the protein folding chaperone, GroEL, also by electron microscopy.