A novel stochastic simulation approach enables exploration of mechanisms for regulating polarity site movement

Ramirez, Samuel A.; Pablo, Michael; Burk, Sean; Lew, Daniel J.; Elston, Timothy C.

doi:10.1101/2020.11.30.404657

Cited by 4 publications

(1 citation statement)

References 64 publications

(124 reference statements)

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“…The URDME approach is also computationally expensive, particularly as the copy numbers of the species increases. We should point out that other approaches exist all with their advantages and disadvantages; see, for example, the description in [ 89 , 90 ].…”

Section: Discussionmentioning

confidence: 99%

Three-dimensional stochastic simulation of chemoattractant-mediated excitability in cells

2021

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During the last decade, a consensus has emerged that the stochastic triggering of an excitable system drives pseudopod formation and subsequent migration of amoeboid cells. The presence of chemoattractant stimuli alters the threshold for triggering this activity and can bias the direction of migration. Though noise plays an important role in these behaviors, mathematical models have typically ignored its origin and merely introduced it as an external signal into a series of reaction-diffusion equations. Here we consider a more realistic description based on a reaction-diffusion master equation formalism to implement these networks. In this scheme, noise arises naturally from a stochastic description of the various reaction and diffusion terms. Working on a three-dimensional geometry in which separate compartments are divided into a tetrahedral mesh, we implement a modular description of the system, consisting of G-protein coupled receptor signaling (GPCR), a local excitation-global inhibition mechanism (LEGI), and signal transduction excitable network (STEN). Our models implement detailed biochemical descriptions whenever this information is available, such as in the GPCR and G-protein interactions. In contrast, where the biochemical entities are less certain, such as the LEGI mechanism, we consider various possible schemes and highlight the differences between them. Our stimulations show that even when the LEGI mechanism displays perfect adaptation in terms of the mean level of proteins, the variance shows a dose-dependence. This differs between the various models considered, suggesting a possible means for determining experimentally among the various potential networks. Overall, our simulations recreate temporal and spatial patterns observed experimentally in both wild-type and perturbed cells, providing further evidence for the excitable system paradigm. Moreover, because of the overall importance and ubiquity of the modules we consider, including GPCR signaling and adaptation, our results will be of interest beyond the field of directed migration.

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Section: Discussionmentioning

confidence: 99%

Three-dimensional stochastic simulation of chemoattractant-mediated excitability in cells

2021

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Speed limits of protein assembly with reversible membrane localization

Mishra

Johnson

2021

The Journal of Chemical Physics

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Protein assembly is often studied in a three-dimensional solution, but a significant fraction of binding events involve proteins that can reversibly bind and diffuse along a two-dimensional surface. In a recent study, we quantified how proteins can exploit the reduced dimensionality of the membrane to trigger complex formation. Here, we derive a single expression for the characteristic timescale of this multi-step assembly process, where the change in dimensionality renders rates and concentrations effectively time-dependent. We find that proteins can accelerate dimer formation due to an increase in relative concentration, driving more frequent collisions, which often win out over slow-downs due to diffusion. Our model contains two protein populations that dimerize with one another and use a distinct site to bind membrane lipids, creating a complex reaction network. However, by identifying two major rate-limiting pathways to reach an equilibrium steady-state, we derive an excellent approximation for the mean first passage time when lipids are in abundant supply. Our theory highlights how the “sticking rate” or effective adsorption coefficient of the membrane is central in controlling timescales. We also derive a corrected localization rate to quantify how the geometry of the system and diffusion can reduce rates of membrane localization. We validate and test our results using kinetic and particle-based reaction-diffusion simulations. Our results establish how the speed of key assembly steps can shift by orders-of-magnitude when membrane localization is possible, which is critical to understanding mechanisms used in cells.

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Chemotactic movement of a polarity site enables yeast cells to find their mates

Ghose

Jacobs

Ramirez

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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How small eukaryotic cells can interpret dynamic, noisy, and spatially complex chemical gradients to orient growth or movement is poorly understood. We address this question using Saccharomyces cerevisiae, where cells orient polarity up pheromone gradients during mating. Initial orientation is often incorrect, but polarity sites then move around the cortex in a search for partners. We find that this movement is biased by local pheromone gradients across the polarity site: that is, movement of the polarity site is chemotactic. A bottom-up computational model recapitulates this biased movement. The model reveals how even though pheromone-bound receptors do not mimic the shape of external pheromone gradients, nonlinear and stochastic effects combine to generate effective gradient tracking. This mechanism for gradient tracking may be applicable to any cell that searches for a target in a complex chemical landscape.

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A novel stochastic simulation approach enables exploration of mechanisms for regulating polarity site movement

Cited by 4 publications

References 64 publications

Three-dimensional stochastic simulation of chemoattractant-mediated excitability in cells

Three-dimensional stochastic simulation of chemoattractant-mediated excitability in cells

Speed limits of protein assembly with reversible membrane localization

Chemotactic movement of a polarity site enables yeast cells to find their mates

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