Research Interests

Model of the transmembrane topology of glutamate receptors which emphasizes the modular structure of these important membrane proteins (from McFeeters & Oswald. FASEB Journal 18: 428-438, 2004).

Fluorine NMR spectroscopy is used to study the dynamics of the ligand binding domain of the GluR2 AMPA receptor. (from Ahmed, Loh, Jane, & Oswald. J. Biol. Chem. 282: 12773-12784, 2007).

Backbone dynamics measurements of the binding domain of the GluR2 AMPA receptor can reveal flexible portions of the structure (from Fenwick & Oswald. J. Molec. Biol. 378: 673-685, 2008).

Our research interests center on the structure and function of proteins involved in signal transduction. These include two important membrane proteins (nicotinic acetylcholine receptors and glutamate receptors) and an intracellular GTP binding protein (Cdc42Hs). Nicotinic acetylcholine and glutamate receptors are large membrane-bound proteins which mediate the flow of ions from the exterior to the interior of a cell following an interaction with a small organic molecule (i.e., an agonist). Acetylcholine receptors are important neurotransmitter receptors in skeletal muscle, the peripheral nervous system, and the central nervous system; glutamate receptors are the primary excitatory neurotransmitter receptors in the vertebrate central nervous system. Cdc42Hs is a soluble protein involved in signaling pathways related to the structure of cytoskeleton.

Nicotinic acetylcholine receptors: Nicotinic acetylcholine receptors are found in electroplaque, skeletal muscle and nerve cells and translate the binding of acetylcholine into the flow of ions across the cell membrane. We are interested in both the nicotinic acetylcholine receptors found in electroplaque/skeletal muscle and the central nervous system. Current studies involve using a combination of specifically designed agonists and antagonists and site-directed mutagenesis of the protein to study the amino acids important for activation and ion flux.

Glutamate receptors: The kainate receptor, a subtype of glutamate receptors, is present in many neurons and is an important neurotransmitter receptor. Several have been cloned in our laboratory and analysis of the glycosylation sites established a new model for the transmembrane topology of these receptors. Current efforts are directed at molecular modeling of these receptors and the use of site-directed mutagenesis to help define the important regions of the binding interface. In addition, NMR spectroscopy is binding used to determine the three dimensional structure of several isolated domains of glutamate receptors. Because of its high concentration in brain and its importance in neuronal excitability, further characterization of this receptor will be of considerable importance to the understanding of epilepsy and neuronal death.

Cdc42Hs and related proteins: GTP binding proteins regulate a wide variety of processes in all living cells. One subtype of this large class of receptors, the rho family of ras-like proteins, seems to be involved in cytoskeletal organization and the mutations in proteins in regulatory pathways in which they function can lead to cell transformation. We are studying the one of these GTP binding proteins, Cdc42Hs, and several of the proteins with which it interacts. We have determined the structure of this protein using heteronuclear, multidimensional NMR spectroscopy and are now focusing on the structure of proteins which regulate Cdc42Hs and the molecular characterization of the binding interfaces.