ArticleProceedings of the National Academy of Sciences of the United States of America2010
Spatio-temporal correlations can drastically change the response of a MAPK pathway.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers.
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111 citing papers in PubMed.
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- Bistable Functions and Signaling Motifs in Systems Chemistry: Taking the Next Step Toward Synthetic Cells.Accounts of chemical research · 2025Review
- Compartmental exchange regulates steady states and stochastic switching of a phosphorylation network.Biophysical journal · 2024Article
- Kinetics of diffusion-influenced multisite phosphorylation with enzyme reactivation.Biopolymers · 2024Article
- Fluorescent biosensors illuminate the spatial regulation of cell signaling across scales.The Biochemical journal · 2023Review
- Endoplasmic reticulum network heterogeneity guides diffusive transport and kinetics.Biophysical journal · 2023Article
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- Diffusive search and trajectories on tubular networks: a propagator approach.The European physical journal. E, Soft matter · 2021Article
- Speed limits of protein assembly with reversible membrane localization.The Journal of chemical physics · 2021Article
- A multiscale compartment-based model of stochastic gene regulatory networks using hitting-time analysis.The Journal of chemical physics · 2021Article
- Concentration sensing in crowded environments.Biophysical journal · 2021Article
- Space-time histories approach to fast stochastic simulation of bimolecular reactions.The Journal of chemical physics · 2021Article
- Quantifying the roles of space and stochasticity in computer simulations for cell biology and cellular biochemistry.Molecular biology of the cell · 2021Article
- Crosstalk and ultrasensitivity in protein degradation pathways.PLoS computational biology · 2020Article
- Strong intracellular signal inactivation produces sharper and more robust signaling from cell membrane to nucleus.PLoS computational biology · 2020Article
- NERDSS: A Nonequilibrium Simulator for Multibody Self-Assembly at the Cellular Scale.Biophysical journal · 2020Article
51 more citing papers are in PubMed but not listed here.
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3 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Multisite covalent modification of proteins is omnipresent in eukaryotic cells. A well-known example is the mitogen-activated protein kinase (MAPK) cascade where, in each layer of the cascade, a protein is phosphorylated at two sites. It has long been known that the response of a MAPK pathway strongly depends on whether the enzymes that modify the protein act processively or distributively. A distributive mechanism, in which the enzyme molecules have to release the substrate molecules in between the modification of the two sites, can generate an ultrasensitive response and lead to hysteresis and bistability. We study by Green's Function Reaction Dynamics (GFRD), a stochastic scheme that makes it possible to simulate biochemical networks at the particle level in time and space, a dual phosphorylation cycle in which the enzymes act according to a distributive mechanism. We find that the response of this network can differ dramatically from that predicted by a mean-field analysis based on the chemical rate equations. In particular, rapid rebindings of the enzyme molecules to the substrate molecules after modification of the first site can markedly speed up the response and lead to loss of ultrasensitivity and bistability. In essence, rapid enzyme-substrate rebindings can turn a distributive mechanism into a processive mechanism. We argue that slow ADP release by the enzymes can protect the system against these rapid rebindings, thus enabling ultrasensitivity and bistability.
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