Large-scale filament formation inhibits the activity of CTP synthetase

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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.

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Rachael Barry

Princeton University, Princeton, United States

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Anne-Florence Bitbol

Princeton University, Princeton, United States

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Alexander Lorestani

Princeton University, Princeton, United States

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Emeric J Charles

McGill University, Montreal, Canada

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Chris H Habrian

University of California, Davis, Davis, United States

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Jesse M Hansen

McGill University, Montreal, Canada

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Hsin-Jung Li

Princeton University, Princeton, United States

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Enoch P Baldwin

University of California, Davis, Davis, United States

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Ned S Wingreen

Princeton University, Princeton, United States

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Justin M Kollman

McGill University, Montreal, Canada

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Zemer Gitai

Princeton University, Princeton, United States

For correspondence
zgitai@princeton.edu

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The authors declare that no competing interests exist.

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