6pk4 | pdb_00006pk4
cryoEM structure of the substrate-bound human CTP synthase 2 filament
Structural highlights
Function[PYRG2_HUMAN] Catalyzes the ATP-dependent amination of UTP to CTP with either L-glutamine or ammonia as the source of nitrogen. Constitutes the rate-limiting enzyme in the synthesis of cytosine nucleotides.[1] [2] Publication Abstract from PubMedMany 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. Coupled structural transitions enable highly cooperative regulation of human CTPS2 filaments.,Lynch EM, Kollman JM Nat Struct Mol Biol. 2019 Dec 23. pii: 10.1038/s41594-019-0352-5. doi:, 10.1038/s41594-019-0352-5. PMID:31873303[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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