The structure of DarB in complex with RelNTD reveals nonribosomal activation of Rel stringent factors
(2023) In Science Advances 9(3). p.1-14- Abstract
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 DarB2:RelNTD2 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... (More)
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 DarB2:RelNTD2 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.
(Less)
- author
- organization
- publishing date
- 2023-01-18
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Science Advances
- volume
- 9
- issue
- 3
- article number
- eade4077
- pages
- 1 - 14
- publisher
- American Association for the Advancement of Science (AAAS)
- external identifiers
-
- scopus:85146485545
- pmid:36652515
- ISSN
- 2375-2548
- DOI
- 10.1126/sciadv.ade4077
- language
- English
- LU publication?
- yes
- id
- 153ce63d-fd4a-42cd-9428-f63ccda88790
- date added to LUP
- 2023-01-20 18:58:39
- date last changed
- 2024-07-27 04:17:01
@article{153ce63d-fd4a-42cd-9428-f63ccda88790, abstract = {{<p>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 DarB2:RelNTD2 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.</p>}}, author = {{Ainelo, Andres and Caballero-Montes, Julien and Bulvas, Ondřej and Ernits, Karin and Coppieters 't Wallant, Kyo and Takada, Hiraku and Craig, Sophie Z and Mazzucchelli, Gabriel and Zedek, Safia and Pichová, Iva and Atkinson, Gemma C and Talavera, Ariel and Martens, Chloe and Hauryliuk, Vasili and Garcia-Pino, Abel}}, issn = {{2375-2548}}, language = {{eng}}, month = {{01}}, number = {{3}}, pages = {{1--14}}, publisher = {{American Association for the Advancement of Science (AAAS)}}, series = {{Science Advances}}, title = {{The structure of DarB in complex with RelNTD reveals nonribosomal activation of Rel stringent factors}}, url = {{http://dx.doi.org/10.1126/sciadv.ade4077}}, doi = {{10.1126/sciadv.ade4077}}, volume = {{9}}, year = {{2023}}, }