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Structures of regulatory machinery reveal novel molecular mechanisms controlling B. subtilis nitrogen homeostasis

  • Author(s): Schumacher, Maria A.
  • Chinnam, Naga babu
  • Cuthbert, Bonnie
  • Tonthat, Nam K.
  • Whitfill, Travis
  • et al.
Abstract

In Bacillus subtilis, nitrogen homeostasis is controlled by a unique circuitry composed of the regulator TnrA and the repressor GlnR. Here, Schumacher et al. describe a comprehensive molecular dissection of this network that reveals novel mechanisms, including oligomeric transformations, by which their inducible signal transduction domains are employed to provide a readout of nitrogen levels.All cells must sense and adapt to changing nutrient availability. However, detailed molecular mechanisms coordinating such regulatory pathways remain poorly understood. In Bacillus subtilis, nitrogen homeostasis is controlled by a unique circuitry composed of the regulator TnrA, which is deactivated by feedback-inhibited glutamine synthetase (GS) during nitrogen excess and stabilized by GlnK upon nitrogen depletion, and the repressor GlnR. Here we describe a complete molecular dissection of this network. TnrA and GlnR, the global nitrogen homeostatic transcription regulators, are revealed as founders of a new structural family of dimeric DNA-binding proteins with C-terminal, flexible, effector-binding sensors that modulate their dimerization. Remarkably, the TnrA sensor domains insert into GS intersubunit catalytic pores, destabilizing the TnrA dimer and causing an unprecedented GS dodecamer-to-tetradecamer conversion, which concomitantly deactivates GS. In contrast, each subunit of the GlnK trimer “templates” active TnrA dimers. Unlike TnrA, GlnR sensors mediate an autoinhibitory dimer-destabilizing interaction alleviated by GS, which acts as a GlnR chaperone. Thus, these studies unveil heretofore unseen mechanisms by which inducible sensor domains drive metabolic reprograming in the model Gram-positive bacterium B. subtilis.

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