All living cells respond to their environment through sensory systems that detect specific changes in the chemistry or in the physical parameters of the environment and transduce these changes into intracellular second messages that change the metabolism and function of the cell. Bacterial chemotaxis is one of the best understood signal transduction systems and it has many characteristics in common with a variety of other signaling systems in microorganisms. Our long term goal is to be able to trace the information transduction process that underlies chemotaxis from ligand binding events through a series of stabilized protein conformational changes, to the mechanisms that lead to amplification and that explain the dynamic range of response of the system and all of the other physiological characteristics that this system displays. We have found that there are specific conserved modules that are expressed as domains of the proteins that interact to generate the chemotaxis signaling circuit. Homologs of these domains are distributed by evolution in a variety of different signaling systems where they play distinct and diverse roles in information processing. One of our goals is to understand exactly how these modules function. In the past, we have made great progress in determining the components of the chemotaxis system, understanding the physiology and behavior of the system and more recently in determining the atomic structure of the proteins involved in chemotaxis. It has become clear that there is a signaling complex that plays a critical role in information processing. Portions of this signaling complex can be reconstituted in vitro and we will study the chemotaxis proteins and genes from the thermophilic bacterium Thermotoga maritima. This system has many interesting characteristics that allow its manipulation in vitro. We have crystal structures for many of the components of the system that are required to generate the signaling complex. We will use a variety of biochemical, molecular biological, and biophysical tools to understand the mechanisms involved in signal transmission, signal generation, protein-protein interaction and information integration by these signaling complexes. This information obtained in vitro in the Thermotoga system will allow us to build specific test molecules that can be used in the E. coli system to correlate the atomic and molecular changes that occur in the signaling complex with the chemotaxis behavior of the organism. These insights will provide an understanding of the parameters that are critical to the function and evolution of microbial signaling systems and that control their versatility and ubiquity. Finally, comparable histidine kinases and signaling complexes are not present in mammalian systems. On the other hand, in many microorganisms and plants, these systems are essential for growth or pathogenesis. Thus, the histidine kinase represents an excellent target for the development of therapeutic agents, e.g. antibiotics, fungicides and herbicides. We will continue to explore this possibility.
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