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-Structure paper
Title | Coupled structural transitions enable highly cooperative regulation of human CTPS2 filaments. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 27, Issue 1, Page 42-48, Year 2020 |
Publish date | Dec 23, 2019 |
Authors | Eric M Lynch / Justin M Kollman / |
PubMed Abstract | 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 ...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. |
External links | Nat Struct Mol Biol / PubMed:31873303 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.1 - 3.5 Å |
Structure data | EMDB-20354, PDB-6pk4: EMDB-20355, PDB-6pk7: |
Chemicals | ChemComp-UTP: ChemComp-ATP: ChemComp-ADP: ChemComp-CTP: |
Source |
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Keywords | PROTEIN FIBRIL / Enzyme / filament |