Product-stabilized filamentation by human glutamine synthetase allosterically tunes metabolic activity
To maintain metabolic homeostasis, enzymes must adapt to fluctuating nutrient levels through mechanisms beyond gene expression. Here, we demonstrate that human glutamine synthetase (GS) can reversibly polymerize into filaments aided by a composite binding site formed at the filament interface by the product, glutamine. Time-resolved cryo-electron microscopy (cryo-EM) confirms that glutamine…
Maintaining metabolic equilibrium requires enzymes to adjust to changing nutrient levels through mechanisms beyond mere gene expression. The researchers have now shown that human glutamine synthetase (GS) can form reversible filaments, which are stabilized by the product, glutamine. Utilizing time-resolved cryo-electron microscopy (cryo-EM), they confirmed that the binding of glutamine to GS results in filament stabilization, leading to a decrease in catalytic specificity for ammonia at physiological levels.
This inhibition is induced by a conformational change in GS that modulates the active site loop ensemble, allowing for substrate entry. Metadynamics ensemble refinement revealed that the active site loop has a 10 Å conformational range, which is stabilized by transient contacts. These transient contacts, crucial for catalysis both in vitro and in cells, are essential because they stabilize the loop in a closed conformation.
The researchers propose that GS filament formation acts as a negative-feedback mechanism, directly linking the concentration of the product to the structural and functional remodeling of the enzyme.
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