Reaction coordinate dependent fibrillar formation of human glutamine synthetase tunes activity.

Abstract

Metabolic enzymes must adapt to changing environments to meet the energetic needs of the cell. Frequently, enzymes form supramolecular fibrils under different metabolic states to regulate function. Here, we show that human glutamine synthetase (GS) is capable of reversibly forming fibril structures along its forward reaction coordinate. In addition to fibril formation, high-resolution cryoEM maps demonstrate coordinated conformational changes that facilitate catalysis. Detailed enzymology and characterization of disease mutations of GS demonstrate an allosteric pathway connecting the active site to the overall enzyme compositional state. Together with a human cell model demonstrating correlated growth phenotype with GS enzymatic activity, we show that GS compositional state changes are a mechanism of enzyme regulation.