My work is focused on understanding the molecular basis of
signaling mechanisms mediated by G proteins, which are switch
proteins. G proteins are normally inactive, but a receptor that has
received a specific signal can activate G proteins, leading to
changes in the activity of enzymes that produce second messengers
such as cyclic AMP and calcium.
The resulting changes in cellular activity underlie a large number of physiological processes. G protein-mediated signalling cascades are key regulators of many physiological processes, including processes of development, differentiation, and regulation of cell division. In the brain, many key neurotransmitters and neuromodulators mediate a myriad of functions by activation of such G protein cascades.
The research in my laboratory is aimed at understanding how G proteins become activated by receptors, how they in turn activate effector enzymes, and how they turn off. We determined the sites of interaction between proteins using a method of decomposing the proteins into small synthetic peptides and determining which peptides blocked interaction sites (Hamm et al., 1988; Rarick et al., 1992; Artemyev et al., 1993; Arshavsky et al., 1994). To understand the process more fully, we determined the atomic structure of the proteins in collaboration with the group of Paul Sigler. We used X-ray crystallography to solve the three-dimensional structures of G proteins in their inactive (GDP bound, (Lambright et al., 1994) and activated (GTPbgS-bound) forms (Noel et al., 1993). We caught a glimpse of the self-inactivating process in another crystal form, the transition state analog, Ga.GDP.AlF4- (Sondek et al., 1994). More recently, the structures of the bg subunit (Sondek et al., 1996) and the heterotrimeric G protein (Lambright et al., 1996) were solved. These high-resolution structural studies allowed us to postulate specific hypotheses regarding mechanisms of receptor:G protein interaction and activation, G protein subunit association-dissociation and effector activation.
The following timeline graph is generated from all co-authored publications.Featured publications are shown below:
No address provided
(615) 343-3533 (p)
MeSH terms are retrieved from PubMed records. Learn more.
Key: MeSH Term KeywordAllosteric Site Apoptosis Biological Transport Cell Communication Chelating Agents Cytosol exocytosis Gastrulation Gene Expression Regulation Gene Expression Regulation, Neoplastic Genetic Vectors Guanine Nucleotides Hippocampus HL-60 Cells Humans Mutation networks of signaling pathways neuromodulation Neurons Osteogenesis Phospholipids Photobiology Platelet Activation Platelet Aggregation Reactive Oxygen Species Receptors, Cell Surface Receptors, Purinergic P2 Retina Retinal Pigments Signal transduction structure and regulation of G-protein signaling Substrate Specificity Synaptic Transmission Up-Regulation vascular biology Xanthines