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Cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation.

<div class='caption-title'>IMPDH structure and function.</div>
<div class='caption-title'>Electron microscopy of uninhibited IMPDH2 filaments.</div>
<div class='caption-title'>A cryo-EM image processing workflow for structure determination of flexible IMPDH2 filaments.</div>
Johnson MC, Kollman JM
OpenAccess logo Elife 9 (2020)
Related entries: 6u8e, 6u8r, 6u8s, 6u9o, 6ua2, 6ua4, 6ua5, 6uaj, 6uc2, 6udo, 6udp, 6udq

Cited: 29 times
EuropePMC logo PMID: 31999252

Abstract

Inosine monophosphate dehydrogenase (IMPDH) mediates the first committed step in guanine nucleotide biosynthesis and plays important roles in cellular proliferation and the immune response. IMPDH reversibly polymerizes in cells and tissues in response to changes in metabolic demand. Self-assembly of metabolic enzymes is increasingly recognized as a general mechanism for regulating activity, typically by stabilizing specific conformations of an enzyme, but the regulatory role of IMPDH filaments has remained unclear. Here, we report a series of human IMPDH2 cryo-EM structures in both active and inactive conformations. The structures define the mechanism of filament assembly, and reveal how filament-dependent allosteric regulation of IMPDH2 makes the enzyme less sensitive to feedback inhibition, explaining why assembly occurs under physiological conditions that require expansion of guanine nucleotide pools. Tuning sensitivity to an allosteric inhibitor distinguishes IMPDH from other metabolic filaments, and highlights the diversity of regulatory outcomes that can emerge from self-assembly.

Articles - 6u8n mentioned but not cited (4)

  1. 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)
  2. Diversity of mechanisms to control bacterial GTP homeostasis by the mutually exclusive binding of adenine and guanine nucleotides to IMP dehydrogenase. Fernández-Justel D, Marcos-Alcalde Í, Abascal F, Vidaña N, Gómez-Puertas P, Jiménez A, Revuelta JL, Buey RM. Protein Sci 31 e4314 (2022)
  3. 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)
  4. research-article Point mutations in IMPDH2 which cause early-onset neurodevelopmental disorders disrupt enzyme regulation and filament structure. O'Neill AG, Burrell AL, Zech M, Elpeleg O, Harel T, Edvardson S, Shaked HM, Rippert AL, Nomakuchi T, Izumi K, Kollman JM. bioRxiv 2023.03.15.532669 (2023)


Reviews citing this publication (6)

  1. Targeting cancer metabolism in the era of precision oncology. Stine ZE, Schug ZT, Salvino JM, Dang CV. Nat Rev Drug Discov 21 141-162 (2022)
  2. Filament formation by metabolic enzymes-A new twist on regulation. Lynch EM, Kollman JM, Webb BA. Curr Opin Cell Biol 66 28-33 (2020)
  3. GTP metabolic reprogramming by IMPDH2: unlocking cancer cells' fuelling mechanism. Kofuji S, Sasaki AT. J Biochem 168 319-328 (2020)
  4. IMPDH dysregulation in disease: a mini review. Burrell AL, Kollman JM. Biochem Soc Trans 50 71-82 (2022)
  5. Greater than the sum of parts: Mechanisms of metabolic regulation by enzyme filaments. Hvorecny KL, Kollman JM. Curr Opin Struct Biol 79 102530 (2023)
  6. The gateway to guanine nucleotides: Allosteric regulation of IMP dehydrogenases. Buey RM, Fernández-Justel D, Jiménez A, Revuelta JL. Protein Sci 31 e4399 (2022)

Articles citing this publication (19)

  1. Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions. Plana-Bonamaisó A, López-Begines S, Fernández-Justel D, Junza A, Soler-Tapia A, Andilla J, Loza-Alvarez P, Rosa JL, Miralles E, Casals I, Yanes O, de la Villa P, Buey RM, Méndez A. Elife 9 e56418 (2020)
  2. Freedom of assembly: metabolic enzymes come together. Simonet JC, Burrell AL, Kollman JM, Peterson JR. Mol Biol Cell 31 1201-1205 (2020)
  3. 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)
  4. 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)
  5. A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells. Cleghorn WM, Burrell AL, Giarmarco MM, Brock DC, Wang Y, Chambers ZS, Du J, Kollman JM, Brockerhoff SE. J Biol Chem 298 101441 (2022)
  6. 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)
  7. 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)
  8. Structural basis of dynamic P5CS filaments. Zhong J, Guo CJ, Zhou X, Chang CC, Yin B, Zhang T, Hu HH, Lu GM, Liu JL. Elife 11 e76107 (2022)
  9. Effect on cell survival and cytoophidium assembly of the adRP-10-related IMPDH1 missense mutation Asp226Asn. Keppeke GD, Chang CC, Zhang Z, Liu JL. Front Cell Dev Biol 11 1234592 (2023)
  10. Letter IMPDH-Based Cytoophidium Structures as Potential Theranostics in Cancer. Keppeke GD, Andrade LEC, Barcelos D, Fernandes M, Landman G. Mol Ther 28 1557-1558 (2020)
  11. Coordinated Formation of IMPDH2 Cytoophidium in Mouse Oocytes and Granulosa Cells. Ni S, Zhang T, Zhou C, Long M, Hou X, You L, Li H, Shi L, Su YQ. Front Cell Dev Biol 9 690536 (2021)
  12. 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)
  13. 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)
  14. Combining multi-omics analysis to identify host-targeted targets for the control of Brucella infection. Yu J, Yuan H, Guo J, Dong Z, Li S, Fu Q, Aode B, Baoyin S, Bao L, Wu L. Microb Biotechnol 16 2345-2366 (2023)
  15. Catalyst-free late-stage functionalization to assemble α-acyloxyenamide electrophiles for selectively profiling conserved lysine residues. Zhao Y, Duan K, Fan Y, Li S, Huang L, Tu Z, Sun H, Cook GM, Yang J, Sun P, Tan Y, Ding K, Li Z. Commun Chem 7 31 (2024)
  16. 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)
  17. The Role of Purine Metabolism-Related Genes PPAT and IMPDH1 in the Carcinogenesis of Intrahepatic Cholangiocarcinoma Based on Metabonomic and Bioinformatic Analyses. Liu CJ, Ma ZZ, Gong WZ, Mao XH, Wen HQ, Wang XH. J Oncol 2023 5141836 (2023)
  18. The mycobacterial guaB1 gene encodes a guanosine 5'-monophosphate reductase with a cystathionine-β-synthase domain. Knejzlík Z, Doležal M, Herkommerová K, Clarova K, Klíma M, Dedola M, Zborníková E, Rejman D, Pichová I. FEBS J 289 5571-5598 (2022)
  19. 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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