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Computational and Experimental Analyses Reveal the Essential Roles of Interdomain Linkers in the Biological Function of Chemotaxis Histidine Kinase CheA
- Wang, Xiqing, Wu, Chun, Vu, Anh, Shea, Joan-Emma, Dahlquist, Frederick W.
- Journal of the American Chemical Society 2012 v.134 no.39 pp. 16107-16110
- bacteria, chemoreceptors, chemotaxis, histidine kinase, models, molecular dynamics, protein phosphorylation, signal transduction
- A two-component signal transduction pathway underlies the phenomenon of bacterial chemotaxis that allows bacteria to modulate their swimming behavior in response to environmental stimuli. The dimeric five-domain histidine kinase, CheA, plays a central role in the pathway, converting sensory signals to a chemical signal via trans-autophosphorylation between the P1 and P4 domains. This autophosphorylation is regulated via the networked interactions among the P5 domain of CheA, CheW, and chemoreceptors. Despite a wealth of structural information about these components and their interactions, the key question of how the kinase activity of the catalytic P4 domain is regulated by the signal received from the regulatory P5 domain remains poorly understood. We performed replica exchange molecular dynamics simulations on the CheA kinase core and found that while individual domains maintained their structural fold, these domains exhibited a variety of interdomain orientations due to two interdomain linkers. A partially populated conformation that adopts an interdomain arrangement is suitable for building a functional ternary complex. An allosteric network derived from this structural model implies critical roles for two linkers in CheA’s activity. The biochemical and biological functions of these linkers were assigned via a series of biochemical and genetic assays that show the P4–P5 linker controls the activation of CheA and the P3–P4 linker controls both the basal autophosphorylation activity and the activation of CheA. These results reveal the functional dependence between the two linkers and the essential role of the linkers in passing signal information from one domain to another.