Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 27, Issue 1, Pages 42-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41594-019-0352-5
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Funding
- US National Institutes of Health [R01 GM118396]
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Many enzymes assemble into defined oligomers, providing a mechanism for cooperatively regulating activity. Recent studies have described a mode of regulation in which enzyme activity is modulated by polymerization into large-scale filaments. Here we describe an ultrasensitive form of polymerization-based regulation employed by human CTP synthase 2 (CTPS2). Cryo-EM structures reveal that CTPS2 filaments dynamically switch between active and inactive forms in response to changes in substrate and product levels. Linking the conformational state of many CTPS2 subunits in a filament results in highly cooperative regulation, greatly exceeding the limits of cooperativity for the CTPS2 tetramer alone. The structures reveal a link between conformation and control of ammonia channeling between the enzyme's active sites, and explain differences in regulation of human CTPS isoforms. This filament-based mechanism of enhanced cooperativity demonstrates how the widespread phenomenon of enzyme polymerization can be adapted to achieve different regulatory outcomes. Cryo-EM and functional analyses of human CTP synthase 2 reveal that this enzyme forms polymeric filaments that can switch between active and inactive forms, in response to substrate and product levels, resulting in highly cooperative regulation.
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