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The nonequilibrium mechanism for ultrasensitivity in a biological switch: sensing by Maxwell's demons.

ABSTRACT: The Escherichia coli flagellar motor senses the intracellular concentration of the response regulator CheY-P and responds by varying the bias between its counterclockwise (CCW) and clockwise (CW) rotational states. The response is ultrasensitive with a large Hill coefficient (approximately 10). Recently, the detailed distribution functions of the CW and the CCW dwell times have been measured for different CW biases. Based on a general result on the properties of the dwell-time statistics for all equilibrium models, we show that the observed dwell-time statistics imply that the flagellar motor switch operates out of equilibrium, with energy dissipation. We propose a dissipative allosteric model that generates dwell-time statistics consistent with the experimental results. Our model reveals a general nonequilibrium mechanism for ultrasensitivity wherein the switch operates with a small energy expenditure to create high sensitivity. In contrast to the conventional equilibrium models, this mechanism does not require one to assume that CheY-P binds to the CCW and CW states with different affinities. The estimated energy consumption by the flagellar motor switch suggests that the transmembrane proton motive force, which drives the motor's rotation, may also power its switching. The existence of net transitional fluxes between microscopic states of the switch is predicted, measurement of these fluxes can test the nonequilibrium model directly. Both the results on the general properties of the dwell-time statistics and the mechanism for ultrasensitivity should be useful for understanding a diverse class of physical and biological systems.

SUBMITTER: Tu Y

PROVIDER: S-EPMC2575293 | biostudies-other | 2008 Aug

REPOSITORIES: biostudies-other

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The nonequilibrium mechanism for ultrasensitivity in a biological switch: sensing by Maxwell's demons.

Tu Yuhai Y

Proceedings of the National Academy of Sciences of the United States of America 20080807 33

The Escherichia coli flagellar motor senses the intracellular concentration of the response regulator CheY-P and responds by varying the bias between its counterclockwise (CCW) and clockwise (CW) rotational states. The response is ultrasensitive with a large Hill coefficient (approximately 10). Recently, the detailed distribution functions of the CW and the CCW dwell times have been measured for different CW biases. Based on a general result on the properties of the dwell-time statistics for all ...[more]

PMID: 18687900

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Project description:Cytokines and lineage-specific transcription factors are critical molecular effectors for terminal differentiation during hematopoiesis. Intrinsic transcription factor activity is often believed to drive commitment and differentiation, whereas cytokine receptor signals have been implicated in the regulation of cell proliferation, survival, and differentiation. In erythropoiesis, recent experimental findings provide direct evidence that erythropoietin (Epo) can generate commitment cues via the erythropoietin receptor (EpoR); specifically, EpoR signaling leads to activation of the transcription factor GATA-1, which then triggers transcription of erythrocyte-specific genes. In particular, activated GATA-1 induces two positive feedback loops in the system through the enhanced expression of both inactive GATA-1 and EpoR, the latter of which is externally regulatable by Epo. Based upon this network architecture, we present a mathematical model of GATA-1 activation by EpoR, which bidirectionally links a lineage-specific receptor and transcription factor. Our deterministic model offers insight into stimulus-response relationships between Epo and several downstream effectors. In addition to the survival signals that EpoR provides, steady-state analysis of our model suggests that receptor upregulation during lineage commitment can also generate ultrasensitivity to Epo and bistability in GATA-1 activity. These system-level properties can induce a switch-like characteristic during differentiation and provide robustness to the mature state. The topology also suggests a novel mechanism for achieving robust bistability in a purely deterministic manner without molecular cooperativity. The analytical solution of a generalized, minimal model is provided and the significance of each of the two positive feedback loops is elucidated through bifurcation analysis. This network topology, or variations thereof, may link other receptor-transcription factor pairs and may therefore be of general relevance in cellular decision-making.

Dataset Information

The nonequilibrium mechanism for ultrasensitivity in a biological switch: sensing by Maxwell's demons.

Publications

The nonequilibrium mechanism for ultrasensitivity in a biological switch: sensing by Maxwell's demons.

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