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The catalytic mechanism of cyclic GMP-AMP synthase (cGAS) and implications for innate immunity and inhibition.

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Hall J, Ralph EC, Shanker S, Wang H, Byrnes LJ, Horst R, Wong J, Brault A, Dumlao D, Smith JF, Dakin LA, Schmitt DC, Trujillo J, Vincent F, Griffor M, Aulabaugh AE
OpenAccess logo Protein Sci 26 2367-2380 (2017)
Related entries: 5vdo, 5vdp, 5vdq, 5vdr, 5vds, 5vdt, 5vdu, 5vdv

Cited: 30 times
EuropePMC logo PMID: 28940468

Abstract

Cyclic GMP-AMP synthase (cGAS) is activated by ds-DNA binding to produce the secondary messenger 2',3'-cGAMP. cGAS is an important control point in the innate immune response; dysregulation of the cGAS pathway is linked to autoimmune diseases while targeted stimulation may be of benefit in immunoncology. We report here the structure of cGAS with dinucleotides and small molecule inhibitors, and kinetic studies of the cGAS mechanism. Our structural work supports the understanding of how ds-DNA activates cGAS, suggesting a site for small molecule binders that may cause cGAS activation at physiological ATP concentrations, and an apparent hotspot for inhibitor binding. Mechanistic studies of cGAS provide the first kinetic constants for 2',3'-cGAMP formation, and interestingly, describe a catalytic mechanism where 2',3'-cGAMP may be a minor product of cGAS compared with linear nucleotides.

Articles - 5vdw mentioned but not cited (3)

  1. Diversity and classification of cyclic-oligonucleotide-based anti-phage signalling systems. Millman A, Melamed S, Amitai G, Sorek R. Nat Microbiol 5 1608-1615 (2020)
  2. The catalytic mechanism of cyclic GMP-AMP synthase (cGAS) and implications for innate immunity and inhibition. Hall J, Ralph EC, Shanker S, Wang H, Byrnes LJ, Horst R, Wong J, Brault A, Dumlao D, Smith JF, Dakin LA, Schmitt DC, Trujillo J, Vincent F, Griffor M, Aulabaugh AE. Protein Sci 26 2367-2380 (2017)
  3. Comparative Study of Interactions between Human cGAS and Inhibitors: Insights from Molecular Dynamics and MM/PBSA Studies. Wang X, Li W. Int J Mol Sci 22 1164 (2021)


Reviews citing this publication (14)

  1. Molecular mechanisms and cellular functions of cGAS-STING signalling. Hopfner KP, Hornung V. Nat Rev Mol Cell Biol 21 501-521 (2020)
  2. STING pathway agonism as a cancer therapeutic. Flood BA, Higgs EF, Li S, Luke JJ, Gajewski TF. Immunol Rev 290 24-38 (2019)
  3. Research Advances in How the cGAS-STING Pathway Controls the Cellular Inflammatory Response. Wan D, Jiang W, Hao J. Front Immunol 11 615 (2020)
  4. Cytosolic DNA sensing by cGAS: regulation, function, and human diseases. Yu L, Liu P. Signal Transduct Target Ther 6 170 (2021)
  5. Cyclic di-AMP, a second messenger of primary importance: tertiary structures and binding mechanisms. He J, Yin W, Galperin MY, Chou SH. Nucleic Acids Res 48 2807-2829 (2020)
  6. cGAS and CD-NTase enzymes: structure, mechanism, and evolution. Kranzusch PJ. Curr Opin Struct Biol 59 178-187 (2019)
  7. Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy. Garland KM, Sheehy TL, Wilson JT. Chem Rev 122 5977-6039 (2022)
  8. Regulation and inhibition of the DNA sensor cGAS. Hertzog J, Rehwinkel J. EMBO Rep 21 e51345 (2020)
  9. Interrupting cyclic dinucleotide-cGAS-STING axis with small molecules. Sintim HO, Mikek CG, Wang M, Sooreshjani MA. Medchemcomm 10 1999-2023 (2019)
  10. Therapeutic Development by Targeting the cGAS-STING Pathway in Autoimmune Disease and Cancer. Li Q, Tian S, Liang J, Fan J, Lai J, Chen Q. Front Pharmacol 12 779425 (2021)
  11. The Evasion of Antiviral Innate Immunity by Chicken DNA Viruses. Gao L, Zheng S, Wang Y. Front Microbiol 12 771292 (2021)
  12. cGAMP-activated cGAS-STING signaling: its bacterial origins and evolutionary adaptation by metazoans. Patel DJ, Yu Y, Xie W. Nat Struct Mol Biol 30 245-260 (2023)
  13. Beyond DNA sensing: expanding the role of cGAS/STING in immunity and diseases. Seok JK, Kim M, Kang HC, Cho YY, Lee HS, Lee JY. Arch Pharm Res 46 500-534 (2023)
  14. Significance of the cGAS-STING Pathway in Health and Disease. Zhou J, Zhuang Z, Li J, Feng Z. Int J Mol Sci 24 13316 (2023)

Articles citing this publication (13)

  1. Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation. Xie W, Lama L, Adura C, Tomita D, Glickman JF, Tuschl T, Patel DJ. Proc Natl Acad Sci U S A 116 11946-11955 (2019)
  2. The allosteric activation of cGAS underpins its dynamic signaling landscape. Hooy RM, Sohn J. Elife 7 e39984 (2018)
  3. Metabolic Targets for Treatment of Autoimmune Diseases. Piranavan P, Bhamra M, Perl A. Immunometabolism 2 e200012 (2020)
  4. Allosteric coupling between Mn2+ and dsDNA controls the catalytic efficiency and fidelity of cGAS. Hooy RM, Massaccesi G, Rousseau KE, Chattergoon MA, Sohn J. Nucleic Acids Res 48 4435-4447 (2020)
  5. A STING-based biosensor affords broad cyclic dinucleotide detection within single living eukaryotic cells. Pollock AJ, Zaver SA, Woodward JJ. Nat Commun 11 3533 (2020)
  6. Alarmones as Vestiges of a Bygone RNA World. Hernández-Morales R, Becerra A, Lazcano A. J Mol Evol 87 37-51 (2019)
  7. A Multi-Enzyme Cascade Reaction for the Production of 2'3'-cGAMP. Becker M, Nikel P, Andexer JN, Lütz S, Rosenthal K. Biomolecules 11 590 (2021)
  8. Catalytic Promiscuity of cGAS: A Facile Enzymatic Synthesis of 2'-3'-Linked Cyclic Dinucleotides. Rosenthal K, Becker M, Rolf J, Siedentop R, Hillen M, Nett M, Lütz S. Chembiochem 21 3225-3228 (2020)
  9. Screening and Identification of Novel cGAS Homologues Using a Combination of in Vitro and In Vivo Protein Synthesis. Rolf J, Siedentop R, Lütz S, Rosenthal K. Int J Mol Sci 21 E105 (2019)
  10. A simple model for determining affinity from irreversible thermal shifts. Hall J. Protein Sci 28 1880-1887 (2019)
  11. The Dengue virus protease NS2B3 cleaves cyclic GMP-AMP synthase to suppress cGAS activation. Bhattacharya M, Bhowmik D, Tian Y, He H, Zhu F, Yin Q. J Biol Chem 299 102986 (2023)
  12. Crystal structure and functional implication of a bacterial cyclic AMP-AMP-GMP synthetase. Ko TP, Wang YC, Tsai CL, Yang CS, Hou MH, Chen Y. Nucleic Acids Res 49 4725-4737 (2021)
  13. STING antagonists, synthesized via Povarov-Doebner type multicomponent reaction. Ong WWS, Dayal N, Chaudhuri R, Lamptey J, Sintim HO. RSC Med Chem 14 1101-1113 (2023)


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