Abstract
To enable the processing of chemical gradients, chemotactic bacteria possess large arrays of transmembrane chemoreceptors, the histidine kinase CheA, and the adaptor protein CheW, organized as coupled core-signaling units (CSU). Despite decades of study, important questions surrounding the molecular mechanisms of sensory signal transduction remain unresolved, owing especially to the lack of a high-resolution CSU structure. Here, we use cryo-electron tomography and sub-tomogram averaging to determine a structure of the Escherichia coli CSU at sub-nanometer resolution. Based on our experimental data, we use molecular simulations to construct an atomistic model of the CSU, enabling a detailed characterization of CheA conformational dynamics in its native structural context. We identify multiple, distinct conformations of the critical P4 domain as well as asymmetries in the localization of the P3 bundle, offering several novel insights into the CheA signaling mechanism.
Highlights
To enable the processing of chemical gradients, chemotactic bacteria possess large arrays of transmembrane chemoreceptors, the histidine kinase CheA, and the adaptor protein CheW, organized as coupled core-signaling units (CSU)
Input to the E. coli chemotaxis pathway is mediated by transmembrane chemoreceptors, which operate as homodimers and respond to specific sets of external chemoeffectors[4,6]
We further investigate the conformational landscape of CheA within the CSU, identifying multiple, distinct conformations of the critical CheA.P4 domain as well as asymmetric conformations of the CheA.P3 bundle, highlighting stabilizing features of each
Summary
To enable the processing of chemical gradients, chemotactic bacteria possess large arrays of transmembrane chemoreceptors, the histidine kinase CheA, and the adaptor protein CheW, organized as coupled core-signaling units (CSU). Chemoreceptors transmit signals across the inner membrane that modulate the autophosphorylation activity of a homodimeric histidine kinase CheA, which is coupled to receptor control by an adaptor protein CheW. Addition or removal of methyl groups at these sites via specific enzymes, modulates the overall level of CheA activity to offset the effects of ligand binding inputs. CheA regulation requires the assembly of core-signaling units (CSUs)[4,13,14] with a well-defined structure, comprising two chemoreceptor trimer-of-dimers (TOD), a single CheA dimer and two CheW monomers (Fig. 1d). Considering the central role that chemotaxis plays in the infection process of numerous human and plant pathogens[24,25,26,27], a detailed characterization of CSU structure and function would, provide an excellent source of novel targets for the development of broadly applicable antimicrobial therapies
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