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The structure of DarB in complex with Rel(NTD) reveals nonribosomal activation of Rel stringent factors
Rel stringent factors are bifunctional ribosome-associated enzymes that catalyze both synthesis and hydrolysis of the alarmones (p)ppGpp. Besides the allosteric control by starved ribosomes and (p)ppGpp, Rel is regulated by various protein factors depending on specific stress conditions, including t...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for the Advancement of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9848473/ https://www.ncbi.nlm.nih.gov/pubmed/36652515 http://dx.doi.org/10.1126/sciadv.ade4077 |
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author | Ainelo, Andres Caballero-Montes, Julien Bulvas, Ondřej Ernits, Karin Coppieters ‘t Wallant, Kyo Takada, Hiraku Craig, Sophie Z. Mazzucchelli, Gabriel Zedek, Safia Pichová, Iva Atkinson, Gemma C. Talavera, Ariel Martens, Chloe Hauryliuk, Vasili Garcia-Pino, Abel |
author_facet | Ainelo, Andres Caballero-Montes, Julien Bulvas, Ondřej Ernits, Karin Coppieters ‘t Wallant, Kyo Takada, Hiraku Craig, Sophie Z. Mazzucchelli, Gabriel Zedek, Safia Pichová, Iva Atkinson, Gemma C. Talavera, Ariel Martens, Chloe Hauryliuk, Vasili Garcia-Pino, Abel |
author_sort | Ainelo, Andres |
collection | PubMed |
description | Rel stringent factors are bifunctional ribosome-associated enzymes that catalyze both synthesis and hydrolysis of the alarmones (p)ppGpp. Besides the allosteric control by starved ribosomes and (p)ppGpp, Rel is regulated by various protein factors depending on specific stress conditions, including the c-di-AMP–binding protein DarB. However, how these effector proteins control Rel remains unknown. We have determined the crystal structure of the DarB(2):Rel(NTD)(2) complex, uncovering that DarB directly engages the SYNTH domain of Rel to stimulate (p)ppGpp synthesis. This association with DarB promotes a SYNTH-primed conformation of the N-terminal domain region, markedly increasing the affinity of Rel for ATP while switching off the hydrolase activity of the enzyme. Binding to c-di-AMP rigidifies DarB, imposing an entropic penalty that precludes DarB-mediated control of Rel during normal growth. Our experiments provide the basis for understanding a previously unknown mechanism of allosteric regulation of Rel stringent factors independent of amino acid starvation. |
format | Online Article Text |
id | pubmed-9848473 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-98484732023-01-30 The structure of DarB in complex with Rel(NTD) reveals nonribosomal activation of Rel stringent factors Ainelo, Andres Caballero-Montes, Julien Bulvas, Ondřej Ernits, Karin Coppieters ‘t Wallant, Kyo Takada, Hiraku Craig, Sophie Z. Mazzucchelli, Gabriel Zedek, Safia Pichová, Iva Atkinson, Gemma C. Talavera, Ariel Martens, Chloe Hauryliuk, Vasili Garcia-Pino, Abel Sci Adv Biomedicine and Life Sciences Rel stringent factors are bifunctional ribosome-associated enzymes that catalyze both synthesis and hydrolysis of the alarmones (p)ppGpp. Besides the allosteric control by starved ribosomes and (p)ppGpp, Rel is regulated by various protein factors depending on specific stress conditions, including the c-di-AMP–binding protein DarB. However, how these effector proteins control Rel remains unknown. We have determined the crystal structure of the DarB(2):Rel(NTD)(2) complex, uncovering that DarB directly engages the SYNTH domain of Rel to stimulate (p)ppGpp synthesis. This association with DarB promotes a SYNTH-primed conformation of the N-terminal domain region, markedly increasing the affinity of Rel for ATP while switching off the hydrolase activity of the enzyme. Binding to c-di-AMP rigidifies DarB, imposing an entropic penalty that precludes DarB-mediated control of Rel during normal growth. Our experiments provide the basis for understanding a previously unknown mechanism of allosteric regulation of Rel stringent factors independent of amino acid starvation. American Association for the Advancement of Science 2023-01-18 /pmc/articles/PMC9848473/ /pubmed/36652515 http://dx.doi.org/10.1126/sciadv.ade4077 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Ainelo, Andres Caballero-Montes, Julien Bulvas, Ondřej Ernits, Karin Coppieters ‘t Wallant, Kyo Takada, Hiraku Craig, Sophie Z. Mazzucchelli, Gabriel Zedek, Safia Pichová, Iva Atkinson, Gemma C. Talavera, Ariel Martens, Chloe Hauryliuk, Vasili Garcia-Pino, Abel The structure of DarB in complex with Rel(NTD) reveals nonribosomal activation of Rel stringent factors |
title | The structure of DarB in complex with Rel(NTD) reveals nonribosomal activation of Rel stringent factors |
title_full | The structure of DarB in complex with Rel(NTD) reveals nonribosomal activation of Rel stringent factors |
title_fullStr | The structure of DarB in complex with Rel(NTD) reveals nonribosomal activation of Rel stringent factors |
title_full_unstemmed | The structure of DarB in complex with Rel(NTD) reveals nonribosomal activation of Rel stringent factors |
title_short | The structure of DarB in complex with Rel(NTD) reveals nonribosomal activation of Rel stringent factors |
title_sort | structure of darb in complex with rel(ntd) reveals nonribosomal activation of rel stringent factors |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9848473/ https://www.ncbi.nlm.nih.gov/pubmed/36652515 http://dx.doi.org/10.1126/sciadv.ade4077 |
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