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Coupled structural transitions enable highly cooperative regulation of human CTPS2 filaments.

<div class='caption-title'>CTPS2 forms distinct S and P-state filaments using the same filament interface.</div>
<div class='caption-title'>Product binding and changes in the tetramer interface in CTPS2 structures.</div>
<div class='caption-title'>UTP binding opens a tunnel connecting the amidoligase and glutaminase active sites in the S-state CTPS2 filament.</div>
Lynch EM, Kollman JM
OpenAccess logo Nat Struct Mol Biol 27 42-48 (2020)
Cited: 31 times
EuropePMC logo PMID: 31873303

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 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.

Articles - 6pk4 mentioned but not cited (3)

  1. Coupled structural transitions enable highly cooperative regulation of human CTPS2 filaments. Lynch EM, Kollman JM. Nat Struct Mol Biol 27 42-48 (2020)
  2. Cryo-EM structures of CTP synthase filaments reveal mechanism of pH-sensitive assembly during budding yeast starvation. Hansen JM, Horowitz A, Lynch EM, Farrell DP, Quispe J, DiMaio F, Kollman JM. Elife 10 e73368 (2021)
  3. Structural basis for isoform-specific inhibition of human CTPS1. Lynch EM, DiMattia MA, Albanese S, van Zundert GCP, Hansen JM, Quispe JD, Kennedy MA, Verras A, Borrelli K, Toms AV, Kaila N, Kreutter KD, McElwee JJ, Kollman JM. Proc Natl Acad Sci U S A 118 e2107968118 (2021)


Reviews citing this publication (4)

  1. Filament formation by metabolic enzymes-A new twist on regulation. Lynch EM, Kollman JM, Webb BA. Curr Opin Cell Biol 66 28-33 (2020)
  2. Greater than the sum of parts: Mechanisms of metabolic regulation by enzyme filaments. Hvorecny KL, Kollman JM. Curr Opin Struct Biol 79 102530 (2023)
  3. GTP-Dependent Regulation of CTP Synthase: Evolving Insights into Allosteric Activation and NH3 Translocation. Bearne SL, Guo CJ, Liu JL. Biomolecules 12 647 (2022)
  4. Agglomeration: when folded proteins clump together. Romero-Romero ML, Garcia-Seisdedos H. Biophys Rev 15 1987-2003 (2023)

Articles citing this publication (24)

  1. Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation. Johnson MC, Kollman JM. Elife 9 e53243 (2020)
  2. Structural basis for ligand binding modes of CTP synthase. Zhou X, Guo CJ, Chang CC, Zhong J, Hu HH, Lu GM, Liu JL. Proc Natl Acad Sci U S A 118 e2026621118 (2021)
  3. Freedom of assembly: metabolic enzymes come together. Simonet JC, Burrell AL, Kollman JM, Peterson JR. Mol Biol Cell 31 1201-1205 (2020)
  4. IMPDH1 retinal variants control filament architecture to tune allosteric regulation. Burrell AL, Nie C, Said M, Simonet JC, Fernández-Justel D, Johnson MC, Quispe J, Buey RM, Peterson JR, Kollman JM. Nat Struct Mol Biol 29 47-58 (2022)
  5. The structure of helical lipoprotein lipase reveals an unexpected twist in lipase storage. Gunn KH, Roberts BS, Wang F, Strauss JD, Borgnia MJ, Egelman EH, Neher SB. Proc Natl Acad Sci U S A 117 10254-10264 (2020)
  6. Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival. Liang JH, Wang C, Yiu SPT, Zhao B, Guo R, Gewurz BE. mBio 12 e0153021 (2021)
  7. Combined Inactivation of CTPS1 and ATR Is Synthetically Lethal to MYC-Overexpressing Cancer Cells. Sun Z, Zhang Z, Wang QQ, Liu JL. Cancer Res 82 1013-1024 (2022)
  8. Filamentation modulates allosteric regulation of PRPS. Hu HH, Lu GM, Chang CC, Li Y, Zhong J, Guo CJ, Zhou X, Yin B, Zhang T, Liu JL. Elife 11 e79552 (2022)
  9. Human PRPS1 filaments stabilize allosteric sites to regulate activity. Hvorecny KL, Hargett K, Quispe JD, Kollman JM. Nat Struct Mol Biol 30 391-402 (2023)
  10. Molecular crowding facilitates bundling of IMPDH polymers and cytoophidium formation. Chang CC, Peng M, Zhong J, Zhang Z, Keppeke GD, Sung LY, Liu JL. Cell Mol Life Sci 79 420 (2022)
  11. CTP synthase polymerization in germline cells of the developing Drosophila egg supports egg production. Simonet JC, Foster MJ, Lynch EM, Kollman JM, Nicholas E, O'Reilly AM, Peterson JR. Biol Open 9 bio050328 (2020)
  12. Nuclear targeted Saccharomyces cerevisiae asparagine synthetases associate with the mitotic spindle regardless of their enzymatic activity. Noree C, Sirinonthanawech N. PLoS One 15 e0243742 (2020)
  13. The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding. Bennett JA, Steward LR, Rudolph J, Voss AP, Aydin H. PLoS Biol 20 e3001899 (2022)
  14. ASNS disruption shortens CTPS cytoophidia in Saccharomyces cerevisiae. Zhang S, Feng HC, Liu JL. G3 (Bethesda) 11 jkaa060 (2021)
  15. Fat body-specific reduction of CTPS alleviates HFD-induced obesity. Liu J, Zhang Y, Wang QQ, Zhou Y, Liu JL. Elife 12 e85293 (2023)
  16. Structural basis of human PRPS2 filaments. Lu GM, Hu HH, Chang CC, Zhong J, Zhou X, Guo CJ, Zhang T, Li YL, Yin B, Liu JL. Cell Biosci 13 100 (2023)
  17. A metal-dependent conformational change provides a structural basis for the inhibition of CTP synthase by gemcitabine-5'-triphosphate. McLeod MJ, Tran N, McCluskey GD, Gillis TD, Bearne SL, Holyoak T. Protein Sci 32 e4648 (2023)
  18. CTP Synthase 1 Is a Novel Therapeutic Target in Lymphoma. Asnagli H, Minet N, Pfeiffer C, Hoeben E, Lane R, Laughton D, Birch L, Jones G, Novak A, Parker AE, Ludwig H, Fischer A, Latour S, Beer PA. Hemasphere 7 e864 (2023)
  19. Neurodevelopmental disorder mutations in the purine biosynthetic enzyme IMPDH2 disrupt its allosteric regulation. O'Neill AG, Burrell AL, Zech M, Elpeleg O, Harel T, Edvardson S, Mor-Shaked H, Rippert AL, Nomakuchi T, Izumi K, Kollman JM. J Biol Chem 299 105012 (2023)
  20. CTP synthase 2 predicts inferior survival and mediates DNA damage response via interacting with BRCA1 in chronic lymphocytic leukemia. Hu X, Han Y, Liu J, Wang H, Tian Z, Zhang X, Zhang Y, Wang X. Exp Hematol Oncol 12 6 (2023)
  21. Cytidine Triphosphate Synthase Four From Arabidopsis thaliana Attenuates Drought Stress Effects. Krämer M, Dörfer E, Hickl D, Bellin L, Scherer V, Möhlmann T. Front Plant Sci 13 842156 (2022)
  22. Differential roles of CTP synthetases CTPS1 and CTPS2 in cell proliferation. Minet N, Boschat AC, Lane R, Laughton D, Beer P, Asnagli H, Soudais C, Bourne T, Fischer A, Martin E, Latour S. Life Sci Alliance 6 e202302066 (2023)
  23. Light-sensitive phosphorylation regulates retinal IMPDH1 activity and filament assembly. Calise SJ, O'Neill AG, Burrell AL, Dickinson MS, Molfino J, Clarke C, Quispe J, Sokolov D, Buey RM, Kollman JM. J Cell Biol 223 e202310139 (2024)
  24. The role of filamentation in activation and DNA sequence specificity of the sequence-specific endonuclease SgrAI. Lyumkis D, Horton NC. Biochem Soc Trans 50 1703-1714 (2022)


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