Abstract
Author SummaryThe ability to respond to environmental stimuli is a universal feature of living cells. Evolution has created a vast array of signalling mechanisms that enable cells to react in many ways to extracellular changes. In bacteria, two-component signalling mechanisms, comprising a sensor protein kinase paired with its a cognate response regulator, are used widely to sense and respond to environmental changes. Some species of bacteria have over 150 different two-component pairs in a single cell, so the specificity between these pairs has to be tightly controlled to prevent “crossed wires” between signalling pathways. In this study, we have identified the determinants of this specificity in a two-component complex that controls the movement of Rhodobacter sphaeroides along a chemical gradient. By solving and analysing the crystal structure of this complex, we were able to pinpoint the amino acid residues that are crucially involved in formation of the complex. Knowledge of these crucial residues allowed us to convert noncognate response regulators into cognate response regulators simply by changing two amino acids. This reengineering of two-component signalling pathways paves the way for producing custom-designed circuits for applications in synthetic biology.
Highlights
Bacteria, Archaea, and some eukaryotes use two-component signalling pathways to detect environmental conditions and bring about appropriate changes in cellular behaviour [1,2]
We present the structure of the Hpt (P1) domain of CheA3 from R. sphaeroides in complex with its cognate response regulator (RR) CheY6, which, to our knowledge, is the first structure of a Hpt domain of a CheA protein in complex with its RR
Twocomponent signalling mechanisms, comprising a sensor protein kinase paired with its a cognate response regulator, are used widely to sense and respond to environmental changes
Summary
Archaea, and some eukaryotes use two-component signalling pathways to detect environmental conditions and bring about appropriate changes in cellular behaviour [1,2]. Twocomponent pathways comprise sensor histidine kinases (HPK) and response regulators (RRs). Environmental stimuli control the rate at which the HPK autophosphorylates on a conserved histidine residue. Some bacteria have over 150 different HPK and RR pairs, and the specificity of the phosphorylation reactions between them needs to be tightly controlled to prevent HPKs from inappropriately phosphorylating and activating noncognate RRs. A number of mechanisms contribute to this specificity [3,4], the primary one is molecular recognition, in which a HPK shows a strong kinetic preference for its cognate RRs [5,6]. Understanding the mechanisms involved in molecular recognition will allow prediction of interacting pairs, but potentially allow the rewiring of bacterial sensory pathways for use in synthetic biology
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