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Receptor noise limitations on chemotactic sensing.

ABSTRACT: Chemotactic eukaryotic cells are able to detect chemoattractant gradients that are both shallow and have a low background concentration. Under these conditions, the noise in the number of bound receptors can be significant and needs to be taken into account in determining the directional sensing process. Here, we quantify numerically the number of bound receptors on the membrane of a disk-shaped cell by using a numerical Monte Carlo tool. The obtained time traces of the receptor occupancy can be used as inputs for any directional sensing model. We investigate the response of the local excitation global inhibition model and a recently developed balanced inactivation model. We determine a measure for the motility of the cell for each model, based on the relevant output variable, as a function of experimental parameters, resulting in several experimentally testable predictions. Furthermore, we show that these two models behave in a qualitatively different fashion when the background concentration is varied. Thus, to properly characterize the sensitivity of cells to receptor occupancy, it is not sufficient to examine the input signal. Rather, one needs to take into account the response of the second messenger pathway.

SUBMITTER: Rappel WJ

PROVIDER: S-EPMC2614751 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Receptor noise limitations on chemotactic sensing.

Rappel Wouter-Jan WJ Levine Herbert H

Proceedings of the National Academy of Sciences of the United States of America 20081208 49

Chemotactic eukaryotic cells are able to detect chemoattractant gradients that are both shallow and have a low background concentration. Under these conditions, the noise in the number of bound receptors can be significant and needs to be taken into account in determining the directional sensing process. Here, we quantify numerically the number of bound receptors on the membrane of a disk-shaped cell by using a numerical Monte Carlo tool. The obtained time traces of the receptor occupancy can be ...[more]

PMID: 19064934

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Project description:Periplasmic binding proteins such as ribose-binding proteins (RBPs) are involved in the bacterial chemotaxis two-component system. RBP selectively identifies and interacts with ribose to induce a conformational change that leads to chemotaxis. Here, we report the development of an engineered Escherichia coli (E. coli) strain expressing a redesigned RBP that can effectively sense cadmium ions and regulate chemotactic movement of cells toward a cadmium ion gradient. RBP was computationally redesigned to bind cadmium ions and produce the conformational change required for chemoreceptor binding. The successful design, CdRBP1, binds to cadmium ions with a dissociation constant of 268 nM. When CdRBP1 was expressed in the periplasmic space of E. coli, the bacteria became live cadmium ion hunters with high selectivity over other divalent metal ions. This work presents an example of making cadmium ions, which are toxic for most organisms, as an attractant to regulate cells movement. Our approach also demonstrates that RBP can be precisely designed to develop metal-detecting living systems for potential applications in synthetic biology and environmental studies. IMPORTANCE Cadmium pollution is one of the major environmental problems due to excessive release and accumulation. New technologies that can auto-detect cadmium ions with good biocompatibility are in urgent need. In this study, we engineered the bacterial chemotaxis system to positively sense cadmium ions by redesigning ribose-binding protein (RBP) to tightly bind cadmium ion and produce the right conformational change for receptor binding and signaling. Our engineered E. coli cells can auto-detect and chase cadmium ions with divalent metal ion selectivity. Many attempts have been carried out to redesign RBP at the ribose binding site with little success. Instead of the ribose binding site, we introduced the cadmium binding site in the opening of the ribose binding pocket by a specially developed computational algorithm. Our design strategy can be applied to engineer live bacteria with autonomous detection and remediation abilities for metal ions or other chemicals in the future.

Project description:BackgroundCells sense chemical spatial gradients and respond by polarizing internal components. This process can be disrupted by gradient noise caused by fluctuations in chemical concentration.ResultsWe investigated how external gradient noise affects spatial sensing and response focusing on noise-filtering and the resultant tradeoffs. First, using a coarse-grained mathematical model of gradient-sensing and cell polarity, we characterized three negative consequences of noise: Inhibition of the extent of polarization, degradation of directional accuracy, and production of a noisy output polarization. Next, we explored filtering strategies and discovered that a combination of positive feedback, multiple signaling stages, and time-averaging produced good results. There was an important tradeoff, however, because filtering resulted in slower polarization. Simulations demonstrated that a two-stage filter-amplifier resulted in a balanced outcome. Then, we analyzed the effect of noise on a mechanistic model of yeast cell polarization in response to gradients of mating pheromone. This analysis showed that yeast cells likely also combine the above three filtering mechanisms into a filter-amplifier structure to achieve impressive spatial-noise tolerance, but with the consequence of a slow response time. Further investigation of the amplifier architecture revealed two positive feedback loops, a fast inner and a slow outer, both of which contributed to noise-tolerant polarization. This model also made specific predictions about how orientation performance depended upon the ratio between the gradient slope (signal) and the noise variance. To test these predictions, we performed microfluidics experiments measuring the ability of yeast cells to orient to shallow gradients of mating pheromone. The results of these experiments agreed well with the modeling predictions, demonstrating that yeast cells can sense gradients shallower than 0.1% ?m-1, approximately a single receptor-ligand molecule difference between front and back, on par with motile eukaryotic cells.ConclusionsSpatial noise impedes the extent, accuracy, and smoothness of cell polarization. A combined filtering strategy implemented by a filter-amplifier architecture with slow dynamics was effective. Modeling and experimental data suggest that yeast cells employ these elaborate mechanisms to filter gradient noise resulting in a slow but relatively accurate polarization response.

Dataset Information

Receptor noise limitations on chemotactic sensing.

Publications

Receptor noise limitations on chemotactic sensing.

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