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Filament Formation Enables Highly Cooperative Regulation of Human CTP Synthase 2
Author(s) -
Lynch Eric,
Kollman Justin
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.01759
Subject(s) - allosteric regulation , cooperativity , chemistry , tetramer , atp synthase , biophysics , enzyme , allosteric enzyme , conformational change , protein filament , biochemistry , biology
CTP synthase is one of a variety of metabolic enzymes recently found to polymerize into large‐scale filaments. CTP synthase catalyzes the ATP‐dependent conversion of UTP to CTP, and is also allosterically regulated by GTP, making it sensitive to levels of all four major ribonucleotides, and therefore an important regulatory node in nucleotide metabolism. For many filament‐forming enzymes, polymerization is driven by binding to substrates, products, or allosteric regulators, and modulates activity by trapping the enzyme in either a high or low activity conformation. Here, we describe a unique, ultrasensitive mechanism of regulation in human CTP synthase 2 (CTPS2) filaments. High‐resolution cryo‐EM structures reveal that rather than selectively stabilizing a single conformation, CTPS2 filaments switch between active and inhibited conformations in response to changes in substrate and product levels. By coupling the conformational state of many CTPS2 subunits within a filament, polymerization greatly enhances the cooperativity of CTPS2 regulation, allowing for more sensitive regulation compared with the CTPS2 tetramer alone. Our cryo‐EM structures of active and inhibited CTPS2 filaments also provide new insight into the mechanism controlling substrate transfer between the enzyme’s two active sites, and further reveal a novel mode of product binding. The ultrasensitive mode of regulation observed in CTPS2 filaments may aid in understanding the function of other enzyme filaments; the coordinated propagation of conformational changes along filaments could provide a mechanism for fine‐tuning the regulation of other polymerizing enzymes.