Molecular choreography of bacterial chemotaxis signalling

For nearly six decades, chemotaxis - a ubiquitous biological behaviour enabling the movement of a cell or organism toward or away from chemicals -has served as a paradigmatic model for the study of cellular sensory signal transduction and motile behavior. The relatively simple chemotaxis machinery of E. coli is the best understood signal transduction system and serves as a powerful tool for investigating the molecular mechanisms that proteins use to detect, process, and transmit signals. The sensory apparatus of E. coli cells is an ordered array of hundreds of basic core signalling units consisting of three essential components, the transmembrane chemoreceptors, the histidine kinase, 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.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. We propose to use a combination of cutting-edge cryoET structural methods and multi-scale molecular simulations, as well as in vivo functional assays, to investigate the structural and dynamical mechanisms underlying signal transduction and regulation. The research plan is divided into three aims:1. Determine the structural basis of signal transduction and array cooperativity2.Define conformational states and dynamics of the array3.Obtain time-resolved structural snapshots of signalling pathwayOur results will establish, in atomistic detail, the chemotaxis signalling pathway that is shared by diverse chemotactic species, including a wide-range of human and plant pathogens, thus impact on multiple disciplines, from antimicrobial drug development to understanding responses to hormones and neurotransmitters in eukaryotic cells.