Large-scale filament formation inhibits the activity of CTP synthetase

eLife

Justin M Kollman¹  Jesse M Hansen²  Emeric J Charles²  Zemer Gitai²  Alexander Lorestani³  Ned S Wingreen³  Rachael M Barry³  Hsin-Jung Li³  Chris H Habrian⁴  Enoch P Baldwin⁴  Anne-Florence Bitbol⁵ 

[1] Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States;Department of Anatomy and Cell Biology, McGill University, Montreal, Canada;Department of Molecular Biology, Princeton University, Princeton, United States;Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States;Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States;

关键词: CTP synthetase;    nucelotide metabolism;    pyrimidine metabolism;    enzyme regulation;   

DOI  :  10.7554/eLife.03638

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown