Cellular signaling pathways involve the integration of multiple signals and have multiple biological outcomes. Many signaling molecules therefore interact with multiple regulators and effectors. This proposal concerns structural, biochemical and genetic studies at two points in signaling pathways (at cross-talk junctions and at membrane) to determine how signaling proteins interact with multiple effectors, the structural basis for interactions between different signaling pathways, and the mechanisms of transmembrane signaling. The Ras oncoprotein is a GTPase which, in its activated or GTP-bound state, interacts with multiple effectors. These effectors include the protein kinase Raf and the Ral guanine nucleotide dissociation stimulator (RalGDS). Previous studies have shown that the Ras-binding domain (RBD) of Raf and the Ras-interacting domain (RID) of RalGDS, although showing little sequence similarity, are structurally similar. The first goal of this research is to solve the structure of the complex between Ras and the Ras-interacting domain of RalGDS to understand the structural basis for the interaction of Ras with multiple effectors and for the cross-talk between the Ras and Ral signaling pathways. This structural information will then be used as a basis for biochemical and genetic studies on effector specificity, the mechanism of RalGDS activation by Ras and the physiological significance of the cross-talk between the Ras and Ral signaling pathways. Some enzyme-linked receptors, such as the insulin and chemotaxis receptors, are oligomeric even in the absence of ligand, and their oligomerization state does not change on ligand binding. Mechanisms of signaling in this class of receptors are in debate. The second goal of this research is to determine by X-ray crystallography the three-dimensional structures of soluble components of bacterial chemotaxis receptors in their signal """"""""on"""""""" and """"""""off"""""""" states. The objective of these studies is to resolve the conflicting evidence about the mechanism of transmembrane signaling in dimeric receptors.
| Kim, Sung-Hou; Wang, Weiru; Kim, Kyeong Kyu (2002) Dynamic and clustering model of bacterial chemotaxis receptors: structural basis for signaling and high sensitivity. Proc Natl Acad Sci U S A 99:11611-5 |
| Falke, J J; Kim, S H (2000) Structure of a conserved receptor domain that regulates kinase activity: the cytoplasmic domain of bacterial taxis receptors. Curr Opin Struct Biol 10:462-9 |
| Zhang, C; Kim, S H (2000) Environment-dependent residue contact energies for proteins. Proc Natl Acad Sci U S A 97:2550-5 |
| Zhang, C; Kim, S H (2000) The effect of dynamic receptor clustering on the sensitivity of biochemical signaling. Pac Symp Biocomput :353-64 |
| Zhang, C; Kim, S H (2000) The anatomy of protein beta-sheet topology. J Mol Biol 299:1075-89 |
