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Co-localization and confinement of ecto-nucleotidases modulate extracellular adenosine nucleotide distributions

Nucleotides comprise small molecules that perform critical signaling roles in biological systems. Adenosine-based nucleotides, including adenosine tri-, di-, and mono-phosphate, are controlled through their rapid degradation by diphosphohydrolases and ecto-nucleotidases (NDAs). The interplay between...

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Autores principales: Rahmaninejad, Hadi, Pace, Tom, Bhatt, Shashank, Sun, Bin, Kekenes-Huskey, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316229/
https://www.ncbi.nlm.nih.gov/pubmed/32584811
http://dx.doi.org/10.1371/journal.pcbi.1007903
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author Rahmaninejad, Hadi
Pace, Tom
Bhatt, Shashank
Sun, Bin
Kekenes-Huskey, Peter
author_facet Rahmaninejad, Hadi
Pace, Tom
Bhatt, Shashank
Sun, Bin
Kekenes-Huskey, Peter
author_sort Rahmaninejad, Hadi
collection PubMed
description Nucleotides comprise small molecules that perform critical signaling roles in biological systems. Adenosine-based nucleotides, including adenosine tri-, di-, and mono-phosphate, are controlled through their rapid degradation by diphosphohydrolases and ecto-nucleotidases (NDAs). The interplay between nucleotide signaling and degradation is especially important in synapses formed between cells, which create signaling ‘nanodomains’. Within these ‘nanodomains’, charged nucleotides interact with densely-packed membranes and biomolecules. While the contributions of electrostatic and steric interactions within such nanodomains are known to shape diffusion-limited reaction rates, less is understood about how these factors control the kinetics of nucleotidase activity. To quantify these factors, we utilized reaction-diffusion numerical simulations of 1) adenosine triphosphate (ATP) hydrolysis into adenosine monophosphate (AMP) and 2) AMP into adenosine (Ado) via two representative nucleotidases, CD39 and CD73. We evaluate these sequentially-coupled reactions in nanodomain geometries representative of extracellular synapses, within which we localize the nucleotidases. With this model, we find that 1) nucleotidase confinement reduces reaction rates relative to an open (bulk) system, 2) the rates of AMP and ADO formation are accelerated by restricting the diffusion of substrates away from the enzymes, and 3) nucleotidase co-localization and the presence of complementary (positive) charges to ATP enhance reaction rates, though the impact of these contributions on nucleotide pools depends on the degree to which the membrane competes for substrates. As a result, these contributions integratively control the relative concentrations and distributions of ATP and its metabolites within the junctional space. Altogether, our studies suggest that CD39 and CD73 nucleotidase activity within junctional spaces can exploit their confinement and favorable electrostatic interactions to finely control nucleotide signaling.
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spelling pubmed-73162292020-06-29 Co-localization and confinement of ecto-nucleotidases modulate extracellular adenosine nucleotide distributions Rahmaninejad, Hadi Pace, Tom Bhatt, Shashank Sun, Bin Kekenes-Huskey, Peter PLoS Comput Biol Research Article Nucleotides comprise small molecules that perform critical signaling roles in biological systems. Adenosine-based nucleotides, including adenosine tri-, di-, and mono-phosphate, are controlled through their rapid degradation by diphosphohydrolases and ecto-nucleotidases (NDAs). The interplay between nucleotide signaling and degradation is especially important in synapses formed between cells, which create signaling ‘nanodomains’. Within these ‘nanodomains’, charged nucleotides interact with densely-packed membranes and biomolecules. While the contributions of electrostatic and steric interactions within such nanodomains are known to shape diffusion-limited reaction rates, less is understood about how these factors control the kinetics of nucleotidase activity. To quantify these factors, we utilized reaction-diffusion numerical simulations of 1) adenosine triphosphate (ATP) hydrolysis into adenosine monophosphate (AMP) and 2) AMP into adenosine (Ado) via two representative nucleotidases, CD39 and CD73. We evaluate these sequentially-coupled reactions in nanodomain geometries representative of extracellular synapses, within which we localize the nucleotidases. With this model, we find that 1) nucleotidase confinement reduces reaction rates relative to an open (bulk) system, 2) the rates of AMP and ADO formation are accelerated by restricting the diffusion of substrates away from the enzymes, and 3) nucleotidase co-localization and the presence of complementary (positive) charges to ATP enhance reaction rates, though the impact of these contributions on nucleotide pools depends on the degree to which the membrane competes for substrates. As a result, these contributions integratively control the relative concentrations and distributions of ATP and its metabolites within the junctional space. Altogether, our studies suggest that CD39 and CD73 nucleotidase activity within junctional spaces can exploit their confinement and favorable electrostatic interactions to finely control nucleotide signaling. Public Library of Science 2020-06-25 /pmc/articles/PMC7316229/ /pubmed/32584811 http://dx.doi.org/10.1371/journal.pcbi.1007903 Text en © 2020 Rahmaninejad et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Rahmaninejad, Hadi
Pace, Tom
Bhatt, Shashank
Sun, Bin
Kekenes-Huskey, Peter
Co-localization and confinement of ecto-nucleotidases modulate extracellular adenosine nucleotide distributions
title Co-localization and confinement of ecto-nucleotidases modulate extracellular adenosine nucleotide distributions
title_full Co-localization and confinement of ecto-nucleotidases modulate extracellular adenosine nucleotide distributions
title_fullStr Co-localization and confinement of ecto-nucleotidases modulate extracellular adenosine nucleotide distributions
title_full_unstemmed Co-localization and confinement of ecto-nucleotidases modulate extracellular adenosine nucleotide distributions
title_short Co-localization and confinement of ecto-nucleotidases modulate extracellular adenosine nucleotide distributions
title_sort co-localization and confinement of ecto-nucleotidases modulate extracellular adenosine nucleotide distributions
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316229/
https://www.ncbi.nlm.nih.gov/pubmed/32584811
http://dx.doi.org/10.1371/journal.pcbi.1007903
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