Large-scale filament formation inhibits the activity of CTP synthetase

Rachael M. Barry, Anne Florence Bitbol, Alexander Lorestani, Emeric J. Charles, Chris H. Habrian, Jesse M. Hansen, Hsin Jung Li, Enoch P. Baldwin, Ned S. Wingreen, Justin M. Kollman, Zemer Gitai

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73 Scopus citations

Abstract

CTP Synthetase (CtpS) is a universally conserved and essential metabolic enzyme. While many enzymes form small oligomers, CtpS forms large-scale filamentous structures of unknown function in prokaryotes and eukaryotes. By simultaneously monitoring CtpS polymerization and enzymatic activity, we show that polymerization inhibits activity, and CtpS's product, CTP, induces assembly. To understand how assembly inhibits activity, we used electron microscopy to define the structure of CtpS polymers. This structure suggests that polymerization sterically hinders a conformational change necessary for CtpS activity. Structure-guided mutagenesis and mathematical modeling further indicate that coupling activity to polymerization promotes cooperative catalytic regulation. This previously uncharacterized regulatory mechanism is important for cellular function since a mutant that disrupts CtpS polymerization disrupts E. coli growth and metabolic regulation without reducing CTP levels. We propose that regulation by large-scale polymerization enables ultrasensitive control of enzymatic activity while storing an enzyme subpopulation in a conformationally restricted form that is readily activatable.

Original languageEnglish (US)
Article numbere03638
Pages (from-to)1-19
Number of pages19
JournaleLife
Volume3
Issue numberJuly2014
DOIs
StatePublished - Jul 16 2014

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Barry, R. M., Bitbol, A. F., Lorestani, A., Charles, E. J., Habrian, C. H., Hansen, J. M., Li, H. J., Baldwin, E. P., Wingreen, N. S., Kollman, J. M., & Gitai, Z. (2014). Large-scale filament formation inhibits the activity of CTP synthetase. eLife, 3(July2014), 1-19. [e03638]. https://doi.org/10.7554/eLife.03638