Assembly and Dynamics of Bacterial Chemosensory Signaling Arrays

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For nearly six decades, chemotaxis - a ubiquitous biological behavior enabling the movement of a cell or organism toward or away from chemicals -has severed as a paradigmatic model for the study of cellular sensory signal transduction and motile behavior. The relatively simple chemotaxis machinery of the bacterium Escherichia coli is the best understood biological signal transduction system and serves as a powerful tool for investigating the molecular mechanisms that proteins use to detect, process, and transmit stimulus information. E. coli cells respond to changes in their chemical environment through a sensory apparatus that is an ordered array (chemosensory array) of hundreds of basic core signalling units consisting of three essential components, the transmembrane chemoreceptors that detects the environment, the histidine kinase that passes the signal to the downstream effector, and the adaptor protein. The core units further assemble into a two-dimensional lattice array which allows cells to amplify and integrate many varied and possibly conflicting signals to locate optimal growing conditions. In bacterial pathogens, chemotaxis response is crucial for colonization and infection. Thus, the signal transduction systems that mediate such responses are potential new targets for antimicrobial drug development. To understand the underlying molecular mechanisms of chemosensory array assembly, activation and high cooperativity, it is essential to determine the precise interactions between the core signalling components, in the context of the array, and its dynamical properties. In this project, we propose to use a combination of cutting-edge cryoEM structural methods and computational modeling and multi-scale molecular simulations, as well as in vivo functional assays for structural validation, to investigate the structural and dynamical mechanisms underlying signal transduction and regulation in the chemosensory array. Our results will establish, in atomistic detail, how individual signals are transmitted across the receptor, adaptively regulated, and subsequently integrated over multiple receptor proteins to jointly affect kinase activity, highlighting general features of cooperative protein signaling. The significant overlap in molecular machinery employed by diverse chemotactic species will greatly extend the relevance of our results, including to signal transduction within a wide-range of human and plant pathogens.