How a cell responds to an extra cellular signal and mounts an intracellular response plays a pivotal role in the life cycle of every cell. Implicit in this statement is the fact that such signaling cascades of mutations within the proteins comprising such cascades can lead to such disease states such as cancer. Much of the information that is conveyed throughout the cell in various signaling cascades propagates in the form of conformational changes in the proteins involved or in changes in the phosphorylation state of signaling proteins.. In addition, proteins a critical role in growth control. The objective of this project is to understand the structural and mechanistic features governing cell growth and cell proliferation.
Three specific aims will utilize protein x-ray crystallography to uncover the stereochemical principles governing growth regulation. First, studies aimed at understanding the mechanisms underlying IkappaB phosphorylation by the IkappaB kinases, IKK1 and IKK2 will be pursued. Second, structural studies of the protein stathmin/oncoprotein-18 will provide a stereochemical microtubule dynamics. Finally, the structural details underlying the chemistry of protein ubiquitination cascades will be examined with regard to both HECT-Domain ubiquitin ligases and a novel E3 class known as the PHD finger. This work will center around structural and functional experiments with the HECT-domain containing E3, WWP1, and the general mechanisms of protein ubiquitination mediated by the complex of the PHD finger of MEKK1 with the E2, UbcH4.
