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The P(II)-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions

P(II), a homotrimeric very ancient and highly widespread (bacteria, archaea, plants) key sensor-transducer protein, conveys signals of abundance or poorness of carbon, energy and usable nitrogen, converting these signals into changes in the activities of channels, enzymes, or of gene expression. P(I...

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Autores principales: Forcada-Nadal, Alicia, Llácer, José Luis, Contreras, Asunción, Marco-Marín, Clara, Rubio, Vicente
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243067/
https://www.ncbi.nlm.nih.gov/pubmed/30483512
http://dx.doi.org/10.3389/fmolb.2018.00091
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author Forcada-Nadal, Alicia
Llácer, José Luis
Contreras, Asunción
Marco-Marín, Clara
Rubio, Vicente
author_facet Forcada-Nadal, Alicia
Llácer, José Luis
Contreras, Asunción
Marco-Marín, Clara
Rubio, Vicente
author_sort Forcada-Nadal, Alicia
collection PubMed
description P(II), a homotrimeric very ancient and highly widespread (bacteria, archaea, plants) key sensor-transducer protein, conveys signals of abundance or poorness of carbon, energy and usable nitrogen, converting these signals into changes in the activities of channels, enzymes, or of gene expression. P(II) sensing is mediated by the P(II) allosteric effectors ATP, ADP (and, in some organisms, AMP), 2-oxoglutarate (2OG; it reflects carbon abundance and nitrogen scarcity) and, in many plants, L-glutamine. Cyanobacteria have been crucial for clarification of the structural bases of P(II) function and regulation. They are the subject of this review because the information gathered on them provides an overall structure-based view of a P(II) regulatory network. Studies on these organisms yielded a first structure of a P(II) complex with an enzyme, (N-acetyl-Lglutamate kinase, NAGK), deciphering how P(II) can cause enzyme activation, and how it promotes nitrogen stockpiling as arginine in cyanobacteria and plants. They have also revealed the first clear-cut mechanism by which P(II) can control gene expression. A small adaptor protein, PipX, is sequestered by P(II) when nitrogen is abundant and is released when is scarce, swapping partner by binding to the 2OG-activated transcriptional regulator NtcA, co-activating it. The structures of P(II)-NAGK, P(II)-PipX, PipX alone, of NtcA in inactive and 2OG-activated forms and as NtcA-2OG-PipX complex, explain structurally P(II) regulatory functions and reveal the changing shapes and interactions of the T-loops of P(II) depending on the partner and on the allosteric effectors bound to P(II). Cyanobacterial studies have also revealed that in the P(II)-PipX complex PipX binds an additional transcriptional factor, PlmA, thus possibly expanding PipX roles beyond NtcA-dependency. Further exploration of these roles has revealed a functional interaction of PipX with PipY, a pyridoxal-phosphate (PLP) protein involved in PLP homeostasis whose mutations in the human ortholog cause epilepsy. Knowledge of cellular levels of the different components of this P(II)-PipX regulatory network and of K(D) values for some of the complexes provides the basic background for gross modeling of the system at high and low nitrogen abundance. The cyanobacterial network can guide searches for analogous components in other organisms, particularly of PipX functional analogs.
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spelling pubmed-62430672018-11-27 The P(II)-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions Forcada-Nadal, Alicia Llácer, José Luis Contreras, Asunción Marco-Marín, Clara Rubio, Vicente Front Mol Biosci Molecular Biosciences P(II), a homotrimeric very ancient and highly widespread (bacteria, archaea, plants) key sensor-transducer protein, conveys signals of abundance or poorness of carbon, energy and usable nitrogen, converting these signals into changes in the activities of channels, enzymes, or of gene expression. P(II) sensing is mediated by the P(II) allosteric effectors ATP, ADP (and, in some organisms, AMP), 2-oxoglutarate (2OG; it reflects carbon abundance and nitrogen scarcity) and, in many plants, L-glutamine. Cyanobacteria have been crucial for clarification of the structural bases of P(II) function and regulation. They are the subject of this review because the information gathered on them provides an overall structure-based view of a P(II) regulatory network. Studies on these organisms yielded a first structure of a P(II) complex with an enzyme, (N-acetyl-Lglutamate kinase, NAGK), deciphering how P(II) can cause enzyme activation, and how it promotes nitrogen stockpiling as arginine in cyanobacteria and plants. They have also revealed the first clear-cut mechanism by which P(II) can control gene expression. A small adaptor protein, PipX, is sequestered by P(II) when nitrogen is abundant and is released when is scarce, swapping partner by binding to the 2OG-activated transcriptional regulator NtcA, co-activating it. The structures of P(II)-NAGK, P(II)-PipX, PipX alone, of NtcA in inactive and 2OG-activated forms and as NtcA-2OG-PipX complex, explain structurally P(II) regulatory functions and reveal the changing shapes and interactions of the T-loops of P(II) depending on the partner and on the allosteric effectors bound to P(II). Cyanobacterial studies have also revealed that in the P(II)-PipX complex PipX binds an additional transcriptional factor, PlmA, thus possibly expanding PipX roles beyond NtcA-dependency. Further exploration of these roles has revealed a functional interaction of PipX with PipY, a pyridoxal-phosphate (PLP) protein involved in PLP homeostasis whose mutations in the human ortholog cause epilepsy. Knowledge of cellular levels of the different components of this P(II)-PipX regulatory network and of K(D) values for some of the complexes provides the basic background for gross modeling of the system at high and low nitrogen abundance. The cyanobacterial network can guide searches for analogous components in other organisms, particularly of PipX functional analogs. Frontiers Media S.A. 2018-11-13 /pmc/articles/PMC6243067/ /pubmed/30483512 http://dx.doi.org/10.3389/fmolb.2018.00091 Text en Copyright © 2018 Forcada-Nadal, Llácer, Contreras, Marco-Marín and Rubio. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Forcada-Nadal, Alicia
Llácer, José Luis
Contreras, Asunción
Marco-Marín, Clara
Rubio, Vicente
The P(II)-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions
title The P(II)-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions
title_full The P(II)-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions
title_fullStr The P(II)-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions
title_full_unstemmed The P(II)-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions
title_short The P(II)-NAGK-PipX-NtcA Regulatory Axis of Cyanobacteria: A Tale of Changing Partners, Allosteric Effectors and Non-covalent Interactions
title_sort p(ii)-nagk-pipx-ntca regulatory axis of cyanobacteria: a tale of changing partners, allosteric effectors and non-covalent interactions
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243067/
https://www.ncbi.nlm.nih.gov/pubmed/30483512
http://dx.doi.org/10.3389/fmolb.2018.00091
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