Research Abstract:
Our laboratory studies signal transduction by G protein-coupled receptors, a superfamily of heptahelical transmembrane proteins. The receptors act as elegantly engineered switches, receiving signals involved in many physiologic processes — blood pressure regulation, glucose homeostasis, sight and smell — to turn on specific signaling cascades within cells. Remarkably, we devote more than 3 percent of our entire genome to encoding these receptors. Despite their widespread importance, we do not understand how the receptors actually function as ligand-activated switches.
We use engineered yeast to apply the power of genetics to the study of signaling by human G protein-coupled receptors. In one strategy, we use saturation mutagenesis to force segments of a chemoattractant receptor to evolve at an extremely high rate. We have generated the largest set of functional mutations within any G protein-coupled receptor. Combined with bioinformatic approaches, this data allows us to build higher-resolution models of the receptor structure. Insights into how ligands activate receptors will aid in drug design and greatly impact medicine; more than half of currently prescribed pharmaceuticals target G protein-coupled receptors.
A new project in the lab focuses on the mechanisms of insulin resistance that are induced by high sugar diets. To understand why hyperglycemia leads to complications of diabetes mellitus, we generated a simple model in Drosophila melanogaster in which high-sugar feeding leads to developmental and metabolic phenotypes. We will use the genetic power of flies to dissect the molecular pathways that are activated by high sugar feeding and that lead to metabolic derangements.
Selected Publications:
Hagemann IS, Miller DL, Klco JM, Nikiforovich GV, and Baranski TJ. Structure of the complement factor 5a (C5a) receptor-ligand complex studied by disulfide trapping and molecular modeling. J Biol Chem 2008 283(12):7763-75.
Bruinsma SP, Cagan RL, and Baranski TJ. Chimaerin and Rac Regulate Cell Number, Adherens Junctions, and EGF Receptor Signaling in the Drosophila Eye. Proc Natl Acad Sci U S A. 2007 104(17):7098-103.
Matsumoto ML, Narzinski K, Nikiforovich GV, Baranski TJ. A comprehensive structure-function map of the intracellular surface of the human C5a receptor: I. Identification of Critical Residues for G protein Activation. J Biol Chem 2007 282(5):3105-21.
Klco JM, Nikiforovich GV, and Baranski TJ. Genetic Analysis of the First and Third Extracellular Loops of the C5a Receptor Reveals an Essential WXFG Motif in the First Loop. J Biol Chem 2006 281(17):12010-12019.
Klco JM, Wiegand CB, Narzinski K, Baranski TJ. Essential role for the second extracellular loop in C5a receptor activation. Nat Struct Mol Biol 2005 12(4):320-326.
Last Updated: 08/13/2008 |