Molecular dissection of the glutamine synthetase-GlnR nitrogen regulatory circuitry in Gram-positive bacteria

Brady A. Travis, Jared V. Peck, Raul Salinas, Brandon Dopkins, Nicholas Lent, Viet D. Nguyen, Mario J. Borgnia, Richard G. Brennan and Maria A. Schumacher ()
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Brady A. Travis: Duke University Medical Center
Jared V. Peck: University of North Carolina
Raul Salinas: Duke University Medical Center
Brandon Dopkins: Duke University Medical Center
Nicholas Lent: Duke University Medical Center
Viet D. Nguyen: Duke University Medical Center
Mario J. Borgnia: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services
Richard G. Brennan: Duke University Medical Center
Maria A. Schumacher: Duke University Medical Center

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract How bacteria sense and respond to nitrogen levels are central questions in microbial physiology. In Gram-positive bacteria, nitrogen homeostasis is controlled by an operon encoding glutamine synthetase (GS), a dodecameric machine that assimilates ammonium into glutamine, and the GlnR repressor. GlnR detects nitrogen excess indirectly by binding glutamine-feedback-inhibited-GS (FBI-GS), which activates its transcription-repression function. The molecular mechanisms behind this regulatory circuitry, however, are unknown. Here we describe biochemical and structural analyses of GS and FBI-GS-GlnR complexes from pathogenic and non-pathogenic Gram-positive bacteria. The structures show FBI-GS binds the GlnR C-terminal domain within its active-site cavity, juxtaposing two GlnR monomers to form a DNA-binding-competent GlnR dimer. The FBI-GS-GlnR interaction stabilizes the inactive GS conformation. Strikingly, this interaction also favors a remarkable dodecamer to tetradecamer transition in some GS, breaking the paradigm that all bacterial GS are dodecamers. These data thus unveil unique structural mechanisms of transcription and enzymatic regulation.

Date: 2022
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DOI: 10.1038/s41467-022-31573-0

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