Differences in regulation mechanisms of glutamine synthetases from methanogenic archaea unveiled by structural investigations
Abstract Glutamine synthetases (GS) catalyze the ATP-dependent ammonium assimilation, the initial step of nitrogen acquisition that must be under tight control to fit cellular needs. While their catalytic mechanisms and regulations are well-characterized in bacteria and eukaryotes, only limited know...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-01-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05726-w |
| _version_ | 1797349791503482880 |
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| author | Marie-Caroline Müller Olivier N. Lemaire Julia M. Kurth Cornelia U. Welte Tristan Wagner |
| author_facet | Marie-Caroline Müller Olivier N. Lemaire Julia M. Kurth Cornelia U. Welte Tristan Wagner |
| author_sort | Marie-Caroline Müller |
| collection | DOAJ |
| description | Abstract Glutamine synthetases (GS) catalyze the ATP-dependent ammonium assimilation, the initial step of nitrogen acquisition that must be under tight control to fit cellular needs. While their catalytic mechanisms and regulations are well-characterized in bacteria and eukaryotes, only limited knowledge exists in archaea. Here, we solved two archaeal GS structures and unveiled unexpected differences in their regulatory mechanisms. GS from Methanothermococcus thermolithotrophicus is inactive in its resting state and switched on by 2-oxoglutarate, a sensor of cellular nitrogen deficiency. The enzyme activation overlays remarkably well with the reported cellular concentration for 2-oxoglutarate. Its binding to an allosteric pocket reconfigures the active site through long-range conformational changes. The homolog from Methermicoccus shengliensis does not harbor the 2-oxoglutarate binding motif and, consequently, is 2-oxoglutarate insensitive. Instead, it is directly feedback-inhibited through glutamine recognition by the catalytic Asp50ʹ-loop, a mechanism common to bacterial homologs, but absent in M. thermolithotrophicus due to residue substitution. Analyses of residue conservation in archaeal GS suggest that both regulations are widespread and not mutually exclusive. While the effectors and their binding sites are surprisingly different, the molecular mechanisms underlying their mode of action on GS activity operate on the same molecular determinants in the active site. |
| first_indexed | 2024-03-08T12:35:32Z |
| format | Article |
| id | doaj.art-8cce51b9400e4b92b36f0e4445b139ee |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-08T12:35:32Z |
| publishDate | 2024-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-8cce51b9400e4b92b36f0e4445b139ee2024-01-21T12:30:45ZengNature PortfolioCommunications Biology2399-36422024-01-017111410.1038/s42003-023-05726-wDifferences in regulation mechanisms of glutamine synthetases from methanogenic archaea unveiled by structural investigationsMarie-Caroline Müller0Olivier N. Lemaire1Julia M. Kurth2Cornelia U. Welte3Tristan Wagner4Microbial Metabolism Research Group, Max Planck Institute for Marine MicrobiologyMicrobial Metabolism Research Group, Max Planck Institute for Marine MicrobiologyDepartment of Microbiology, Radboud Institute for Biological and Environmental Sciences, Radboud UniversityDepartment of Microbiology, Radboud Institute for Biological and Environmental Sciences, Radboud UniversityMicrobial Metabolism Research Group, Max Planck Institute for Marine MicrobiologyAbstract Glutamine synthetases (GS) catalyze the ATP-dependent ammonium assimilation, the initial step of nitrogen acquisition that must be under tight control to fit cellular needs. While their catalytic mechanisms and regulations are well-characterized in bacteria and eukaryotes, only limited knowledge exists in archaea. Here, we solved two archaeal GS structures and unveiled unexpected differences in their regulatory mechanisms. GS from Methanothermococcus thermolithotrophicus is inactive in its resting state and switched on by 2-oxoglutarate, a sensor of cellular nitrogen deficiency. The enzyme activation overlays remarkably well with the reported cellular concentration for 2-oxoglutarate. Its binding to an allosteric pocket reconfigures the active site through long-range conformational changes. The homolog from Methermicoccus shengliensis does not harbor the 2-oxoglutarate binding motif and, consequently, is 2-oxoglutarate insensitive. Instead, it is directly feedback-inhibited through glutamine recognition by the catalytic Asp50ʹ-loop, a mechanism common to bacterial homologs, but absent in M. thermolithotrophicus due to residue substitution. Analyses of residue conservation in archaeal GS suggest that both regulations are widespread and not mutually exclusive. While the effectors and their binding sites are surprisingly different, the molecular mechanisms underlying their mode of action on GS activity operate on the same molecular determinants in the active site.https://doi.org/10.1038/s42003-023-05726-w |
| spellingShingle | Marie-Caroline Müller Olivier N. Lemaire Julia M. Kurth Cornelia U. Welte Tristan Wagner Differences in regulation mechanisms of glutamine synthetases from methanogenic archaea unveiled by structural investigations Communications Biology |
| title | Differences in regulation mechanisms of glutamine synthetases from methanogenic archaea unveiled by structural investigations |
| title_full | Differences in regulation mechanisms of glutamine synthetases from methanogenic archaea unveiled by structural investigations |
| title_fullStr | Differences in regulation mechanisms of glutamine synthetases from methanogenic archaea unveiled by structural investigations |
| title_full_unstemmed | Differences in regulation mechanisms of glutamine synthetases from methanogenic archaea unveiled by structural investigations |
| title_short | Differences in regulation mechanisms of glutamine synthetases from methanogenic archaea unveiled by structural investigations |
| title_sort | differences in regulation mechanisms of glutamine synthetases from methanogenic archaea unveiled by structural investigations |
| url | https://doi.org/10.1038/s42003-023-05726-w |
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