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TitleCoupled structural transitions enable highly cooperative regulation of human CTPS2 filaments.
Journal, issue, pagesNat Struct Mol Biol, Vol. 27, Issue 1, Page 42-48, Year 2020
Publish dateDec 23, 2019
AuthorsEric M Lynch / Justin M Kollman /
PubMed AbstractMany 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 linksNat Struct Mol Biol / PubMed:31873303 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.5 Å
Structure data

EMDB-20354, PDB-6pk4:
cryoEM structure of the substrate-bound human CTP synthase 2 filament
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-20355, PDB-6pk7:
cryoEM structure of the product-bound human CTP synthase 2 filament
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-UTP:
URIDINE 5'-TRIPHOSPHATE / UTP*YM / Uridine triphosphate

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

ChemComp-CTP:
CYTIDINE-5'-TRIPHOSPHATE / Cytidine triphosphate

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / Enzyme / filament

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