Project description
Structural basis and dynamics of bacterial chemotaxis signalling
The relatively simple chemotaxis machinery of Escherichia coli serves as a model for investigating the molecular mechanisms of cellular sensory signal transduction and motile behaviour. The sensory apparatus is formed by an array of hundreds of core signalling units, consisting of the transmembrane chemoreceptors, the histidine kinase and the adaptor protein. The two-dimensional lattice array allows cells to amplify and integrate different signals, finding optimal growing conditions. The EU-funded ChemoTaxi project aims to investigate the structural and dynamical mechanisms underlying signal transduction, regulation, chemosensory array assembly and activation. The project will employ cryogenic electron tomography, multiscale molecular simulations and functional assays to determine the structure and dynamics of the array and obtain time-resolved snapshots of the signalling pathway.
Objective
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 cooperativity
2. Define conformational states and dynamics of the array
3. Obtain time-resolved structural snapshots of signalling pathway
Our 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.
Fields of science
Not validated
Not validated
Programme(s)
Topic(s)
Funding Scheme
ERC-ADG - Advanced GrantHost institution
0X11 0DE Didcot
United Kingdom