Abstract
Two-component signal transduction systems, where the phosphorylation state of a regulator protein is modulated by a sensor kinase, are common in bacteria and other microbes. In many of these systems, the sensor kinase is bifunctional catalyzing both, the phosphorylation and the dephosphorylation of the regulator protein in response to input signals. Previous studies have shown that systems with a bifunctional enzyme can adjust the phosphorylation level of the regulator protein independently of the total protein concentrations – a property known as concentration robustness. Here, I argue that two-component systems with a bifunctional enzyme may also exhibit ultrasensitivity if the input signal reciprocally affects multiple activities of the sensor kinase. To this end, I consider the case where an allosteric effector inhibits autophosphorylation and, concomitantly, activates the enzyme's phosphatase activity, as observed experimentally in the PhoQ/PhoP and NRII/NRI systems. A theoretical analysis reveals two operating regimes under steady state conditions depending on the effector affinity: If the affinity is low the system produces a graded response with respect to input signals and exhibits stimulus-dependent concentration robustness – consistent with previous experiments. In contrast, a high-affinity effector may generate ultrasensitivity by a similar mechanism as phosphorylation-dephosphorylation cycles with distinct converter enzymes. The occurrence of ultrasensitivity requires saturation of the sensor kinase's phosphatase activity, but is restricted to low effector concentrations, which suggests that this mode of operation might be employed for the detection and amplification of low abundant input signals. Interestingly, the same mechanism also applies to covalent modification cycles with a bifunctional converter enzyme, which suggests that reciprocal regulation, as a mechanism to generate ultrasensitivity, is not restricted to two-component systems, but may apply more generally to bifunctional enzyme systems.
Highlights
Two-component systems (TCSs) are modular signal transduction systems which are utilized by bacteria and other microbes to respond to intracellular or environmental stimuli [1,2]
TCSs consist of a sensor histidine kinase (HK) and a cognate response regulator (RR), which often acts as a transcription factor to activate or repress a particular set of response genes
Since Cp *Kp, increasing Kp leads to an increased value of Cp so that the asymptotically constant phosphorylation level of PhoB{P&CpF20D is reached at higher total PhoB concentrations, i.e. for total PhoB&10 pmol (Fig. 3A)
Summary
Two-component systems (TCSs) are modular signal transduction systems which are utilized by bacteria and other microbes to respond to intracellular or environmental stimuli [1,2]. Even though the overall signal flow from the sensor kinase to the response regulator is well-conserved between different systems there exist substantial variations in the particular mechanism through which the phosphoryl group is transferred to the regulator protein [3] To better understand their regulatory properties it has opposing activities [14,15]. Based on this argument it, appears unlikely that classical two-component systems with a bifunctional sensor kinase would exhibit ultrasensitivity given that the phosphotransferase and phosphatase activities of the sensor kinase are believed to occur on a single catalytic site in the dimerization domain of the protein [16,17]. This conclusion does not apply to bifunctional enzymes with two distinct catalytic sites where ultrasensitivity may arise from the formation of a ternary complex between the enzyme and its two substrates [18] as observed experimentally in the uridylylation cycle of the PII protein [19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
