04. December 2014, 16:00
Ernst-Abbe-Platz 2, seminar room 3423
Ultrasensitivity and concentration robustness in bifunctional enzyme systems
Dr. Ronny Straube
(Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg)
Regulation by covalent modification is a common mechanism to transmit signals in biological reaction networks. Intriguingly, there exist two architectures for this purpose: Either modification and demodification are catalyzed by distinct converter enzymes or both reactions are carried out by a single bifunctional enzyme. Based on theoretical studies it has been argued that (zero- order) ultrasensitivity can be generated by systems with two converter enzymes. Instead, a bifunctional design has been associated with a particular form of input-output robustness known as concentration robustness. However, experiments indicate that bifunctional enzyme systems may also exhibit ultrasensitivity raising the question about the underlying mechanism. Here, I show that this apparent discrepancy can be reconciled if the bifunctional enzyme exhibits two catalytic sites for its opposing activities. In that case, it depends on the kinetic operating regime of the enzyme activities whether concentration robustness or ultrasensitivity can be observed [1].
In the second part of the talk I will propose a mechanism that may lead to ultrasensitivity in bacterial two-component systems where the phosphorylation of a response regulator occurs by a bifunctional sensor kinase. While concentration robustness is now a well-established concept for two-component systems it is generally believed that they would generate graded rather than ultrasensitive responses to input signals. Here, I argue that this is not necessarily the case if the input signal reciprocally affects multiple activities of the sensor kinase. To this end, I analyze an extension of the Batchelor-Goulian model [2] which shows that ultrasensitivity may occur if the autokinase and phosphatase activities of the sensor kinase are reciprocally regulated by an allosteric effector of sufficiently high affinity [3]. In contrast, a low-affinity effector generates concentration robustness which is predicted to occur in a stimulus-dependent manner. Together, these results extend our quantitative understanding of the response behavior of two-component systems to input signals. They may also guide the design of synthetic regulatory circuits which aim to implement ultrasensitive behavior at the level of two-component systems.
[1] Straube R (2013) Sensitivity and robustness in covalent modification cycles with a bifunctional converter enzyme. Biophys J 105 1925 – 1933.
[2] Batchelor E & Goulian M (2003) Robustness and the cycle of phosphorylation and dephosphorylation in a two-component regulatory system. PNAS 100 691 – 696.
[3] Straube R (2014) Reciprocal regulation as a source of ultrasensitivity in two-component systems with a bifunctional sensor kinase. PLoS Comput Biol 10 e1003614.