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The mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP.

Zhu CF, Wei W, Peng X, Dong YH, Gong Y, Yu XF
Acta Crystallogr D Biol Crystallogr 71 516-24 (2015)
Related entries: 4rxo, 4rxq, 4rxr, 4rxs

Cited: 30 times
EuropePMC logo PMID: 25760601

Abstract

SAMHD1 is the only known eukaryotic deoxynucleoside triphosphate triphosphohydrolase (dNTPase) and is a major regulator of intracellular dNTP pools. It has been reported to be a potent inhibitor of retroviruses such as HIV-1 and endogenous retrotransposons. Previous crystal structures have revealed that SAMHD1 is activated by dGTP-dependent tetramer formation. However, recent data have indicated that the primary activator of SAMHD1 is GTP, not dGTP. Therefore, how its dNTPase activity is regulated needs to be further clarified. Here, five crystal structures of the catalytic core of SAMHD1 in complex with different combinations of GTP and dNTPs are reported, including a GTP-bound dimer and four GTP/dNTP-bound tetramers. The data show that human SAMHD1 contains two unique activator-binding sites in the allosteric pocket. The primary activator GTP binds to one site and the substrate dNTP (dATP, dCTP, dUTP or dTTP) occupies the other. Consequently, both GTP and dNTP are required for tetramer activation of the enzyme. In the absence of substrate binding, SAMHD1 adopts an inactive dimer conformation even when complexed with GTP. Furthermore, SAMHD1 activation is regulated by the concentration of dNTP. Thus, the level of dNTP pools is elegantly regulated by the self-sensing ability of SAMHD1 through a novel activation mechanism.

Reviews - 4rxp mentioned but not cited (1)

  1. The missing link: allostery and catalysis in the anti-viral protein SAMHD1. Morris ER, Taylor IA. Biochem Soc Trans 47 1013-1027 (2019)

Articles - 4rxp mentioned but not cited (1)

  1. Biochemical functions and structure of Caenorhabditis elegans ZK177.8 protein: Aicardi-Goutières syndrome SAMHD1 dNTPase ortholog. Maehigashi T, Lim C, Wade LR, Bowen NE, Knecht KM, Alvarez NN, Kelly WG, Schinazi RF, Kim DH, Xiong Y, Kim B. J Biol Chem 299 105148 (2023)


Reviews citing this publication (9)

  1. SAMHD1 Functions and Human Diseases. Coggins SA, Mahboubi B, Schinazi RF, Kim B. Viruses 12 E382 (2020)
  2. SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity. Mauney CH, Hollis T. Autoimmunity 51 96-110 (2018)
  3. Roles of SAMHD1 in antiviral defense, autoimmunity and cancer. Li M, Zhang D, Zhu M, Shen Y, Wei W, Ying S, Korner H, Li J. Rev Med Virol 27 (2017)
  4. The druggability of intracellular nucleotide-degrading enzymes. Rampazzo C, Tozzi MG, Dumontet C, Jordheim LP. Cancer Chemother Pharmacol 77 883-893 (2016)
  5. Functional organization of human SAMHD1 and mechanisms of HIV-1 restriction. Ahn J. Biol Chem 397 373-379 (2016)
  6. SAMHD1 … and Viral Ways around It. Deutschmann J, Gramberg T. Viruses 13 395 (2021)
  7. Targeting the DNA damage response and repair in cancer through nucleotide metabolism. Helleday T, Rudd SG. Mol Oncol 16 3792-3810 (2022)
  8. Mechanistic cross-talk between DNA/RNA polymerase enzyme kinetics and nucleotide substrate availability in cells: Implications for polymerase inhibitor discovery. Coggins SA, Mahboubi B, Schinazi RF, Kim B. J Biol Chem 295 13432-13443 (2020)
  9. Mechanistic Interplay between HIV-1 Reverse Transcriptase Enzyme Kinetics and Host SAMHD1 Protein: Viral Myeloid-Cell Tropism and Genomic Mutagenesis. Bowen NE, Oo A, Kim B. Viruses 14 1622 (2022)

Articles citing this publication (19)

  1. Effects of T592 phosphomimetic mutations on tetramer stability and dNTPase activity of SAMHD1 can not explain the retroviral restriction defect. Bhattacharya A, Wang Z, White T, Buffone C, Nguyen LA, Shepard CN, Kim B, Demeler B, Diaz-Griffero F, Ivanov DN. Sci Rep 6 31353 (2016)
  2. The SAMHD1 dNTP Triphosphohydrolase Is Controlled by a Redox Switch. Mauney CH, Rogers LC, Harris RS, Daniel LW, Devarie-Baez NO, Wu H, Furdui CM, Poole LB, Perrino FW, Hollis T. Antioxid Redox Signal 27 1317-1331 (2017)
  3. With me or against me: Tumor suppressor and drug resistance activities of SAMHD1. Herold N, Rudd SG, Sanjiv K, Kutzner J, Myrberg IH, Paulin CBJ, Olsen TK, Helleday T, Henter JI, Schaller T. Exp Hematol 52 32-39 (2017)
  4. Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy. Rudd SG, Tsesmetzis N, Sanjiv K, Paulin CB, Sandhow L, Kutzner J, Hed Myrberg I, Bunten SS, Axelsson H, Zhang SM, Rasti A, Mäkelä P, Coggins SA, Tao S, Suman S, Branca RM, Mermelekas G, Wiita E, Lee S, Walfridsson J, Schinazi RF, Kim B, Lehtiö J, Rassidakis GZ, Pokrovskaja Tamm K, Warpman-Berglund U, Heyman M, Grandér D, Lehmann S, Lundbäck T, Qian H, Henter JI, Schaller T, Helleday T, Herold N. EMBO Mol Med 12 e10419 (2020)
  5. The structural basis for cancer drug interactions with the catalytic and allosteric sites of SAMHD1. Knecht KM, Buzovetsky O, Schneider C, Thomas D, Srikanth V, Kaderali L, Tofoleanu F, Reiss K, Ferreirós N, Geisslinger G, Batista VS, Ji X, Cinatl J, Keppler OT, Xiong Y. Proc Natl Acad Sci U S A 115 E10022-E10031 (2018)
  6. Crystal structures of SAMHD1 inhibitor complexes reveal the mechanism of water-mediated dNTP hydrolysis. Morris ER, Caswell SJ, Kunzelmann S, Arnold LH, Purkiss AG, Kelly G, Taylor IA. Nat Commun 11 3165 (2020)
  7. A Highly Active Isoform of Lentivirus Restriction Factor SAMHD1 in Mouse. Bloch N, Gläsker S, Sitaram P, Hofmann H, Shepard CN, Schultz ML, Kim B, Landau NR. J Biol Chem 292 1068-1080 (2017)
  8. Allosteric Activation of SAMHD1 Protein by Deoxynucleotide Triphosphate (dNTP)-dependent Tetramerization Requires dNTP Concentrations That Are Similar to dNTP Concentrations Observed in Cycling T Cells. Wang Z, Bhattacharya A, Villacorta J, Diaz-Griffero F, Ivanov DN. J Biol Chem 291 21407-21413 (2016)
  9. Substrate Specificity of SAMHD1 Triphosphohydrolase Activity Is Controlled by Deoxyribonucleoside Triphosphates and Phosphorylation at Thr592. Jang S, Zhou X, Ahn J. Biochemistry 55 5635-5646 (2016)
  10. A Cyclin-Binding Motif in Human SAMHD1 Is Required for Its HIV-1 Restriction, dNTPase Activity, Tetramer Formation, and Efficient Phosphorylation. St Gelais C, Kim SH, Maksimova VV, Buzovetsky O, Knecht KM, Shepard C, Kim B, Xiong Y, Wu L. J Virol 92 e01787-17 (2018)
  11. Functionality of Redox-Active Cysteines Is Required for Restriction of Retroviral Replication by SAMHD1. Wang Z, Bhattacharya A, White T, Buffone C, McCabe A, Nguyen LA, Shepard CN, Pardo S, Kim B, Weintraub ST, Demeler B, Diaz-Griffero F, Ivanov DN. Cell Rep 24 815-823 (2018)
  12. Identification of Inhibitors of the dNTP Triphosphohydrolase SAMHD1 Using a Novel and Direct High-Throughput Assay. Mauney CH, Perrino FW, Hollis T. Biochemistry 57 6624-6636 (2018)
  13. Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses. Banchenko S, Krupp F, Gotthold C, Bürger J, Graziadei A, O'Reilly FJ, Sinn L, Ruda O, Rappsilber J, Spahn CMT, Mielke T, Taylor IA, Schwefel D. PLoS Pathog 17 e1009775 (2021)
  14. The C-terminal domain of feline and bovine SAMHD1 proteins has a crucial role in lentiviral restriction. Wang C, Zhang K, Meng L, Zhang X, Song Y, Zhang Y, Gai Y, Zhang Y, Yu B, Wu J, Wang S, Yu X. J Biol Chem 295 4252-4264 (2020)
  15. Probing the Catalytic Mechanism and Inhibition of SAMHD1 Using the Differential Properties of Rp- and Sp-dNTPαS Diastereomers. Morris ER, Kunzelmann S, Caswell SJ, Purkiss AG, Kelly G, Taylor IA. Biochemistry 60 1682-1698 (2021)
  16. Molecular dynamics characterization of the SAMHD1 Aicardi-Goutières Arg145Gln mutant: structural determinants for the impaired tetramerization. Cardamone F, Falconi M, Desideri A. J Comput Aided Mol Des 32 623-632 (2018)
  17. Role of Intracellular Distribution of Feline and Bovine SAMHD1 Proteins in Lentiviral Restriction. Wang C, Meng L, Wang J, Zhang K, Duan S, Ren P, Wei Y, Fu X, Yu B, Wu J, Yu X. Virol Sin 36 981-996 (2021)
  18. Deoxyguanosine-Linked Bifunctional Inhibitor of SAMHD1 dNTPase Activity and Nucleic Acid Binding. Egleston M, Dong L, Howlader AH, Bhat S, Orris B, Bianchet MA, Greenberg MM, Stivers JT. ACS Chem Biol 18 2200-2210 (2023)
  19. Protein oxidation increases SAMHD1 binding ssDNA via its regulatory site. Simermeyer TL, Batalis S, Rogers LC, Zalesak OJ, Hollis T. Nucleic Acids Res 51 7014-7024 (2023)


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