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Structural basis of allosteric activation of sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) by nucleoside triphosphates.

Koharudin LM, Wu Y, DeLucia M, Mehrens J, Gronenborn AM, Ahn J
J Biol Chem 289 32617-27 (2014)
Related entries: 4qfx, 4qfz, 4qg0, 4qg1, 4qg2, 4qg4

Cited: 44 times
EuropePMC logo PMID: 25288794

Abstract

Sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) plays a critical role in inhibiting HIV infection, curtailing the pool of dNTPs available for reverse transcription of the viral genome. Recent structural data suggested a compelling mechanism for the regulation of SAMHD1 enzymatic activity and revealed dGTP-induced association of two inactive dimers into an active tetrameric enzyme. Here, we present the crystal structures of SAMHD1 catalytic core (residues 113-626) tetramers, complexed with mixtures of nucleotides, including dGTP/dATP, dGTP/dCTP, dGTP/dTTP, and dGTP/dUTP. The combined structural and biochemical data provide insight into dNTP promiscuity at the secondary allosteric site and how enzymatic activity is modulated. In addition, we present biochemical analyses of GTP-induced SAMHD1 full-length tetramerization and the structure of SAMHD1 catalytic core tetramer in complex with GTP/dATP, revealing the structural basis of GTP-mediated SAMHD1 activation. Altogether, the data presented here advance our understanding of SAMHD1 function during cellular homeostasis.

Articles - 4qfy mentioned but not cited (1)

  1. Structural basis of allosteric activation of sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) by nucleoside triphosphates. Koharudin LM, Wu Y, DeLucia M, Mehrens J, Gronenborn AM, Ahn J. J Biol Chem 289 32617-32627 (2014)


Reviews citing this publication (11)

  1. Deoxyribonucleotide metabolism, mutagenesis and cancer. Mathews CK. Nat Rev Cancer 15 528-539 (2015)
  2. HIV suppression by host restriction factors and viral immune evasion. Jia X, Zhao Q, Xiong Y. Curr Opin Struct Biol 31 106-114 (2015)
  3. SAMHD1 Functions and Human Diseases. Coggins SA, Mahboubi B, Schinazi RF, Kim B. Viruses 12 E382 (2020)
  4. SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity. Mauney CH, Hollis T. Autoimmunity 51 96-110 (2018)
  5. Dendritic Cells, the Double Agent in the War Against HIV-1. Martín-Moreno A, Muñoz-Fernández MA. Front Immunol 10 2485 (2019)
  6. 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)
  7. Functional organization of human SAMHD1 and mechanisms of HIV-1 restriction. Ahn J. Biol Chem 397 373-379 (2016)
  8. The missing link: allostery and catalysis in the anti-viral protein SAMHD1. Morris ER, Taylor IA. Biochem Soc Trans 47 1013-1027 (2019)
  9. SAMHD1 … and Viral Ways around It. Deutschmann J, Gramberg T. Viruses 13 395 (2021)
  10. Targeting the DNA damage response and repair in cancer through nucleotide metabolism. Helleday T, Rudd SG. Mol Oncol 16 3792-3810 (2022)
  11. 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 (32)

  1. SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Schneider C, Oellerich T, Baldauf HM, Schwarz SM, Thomas D, Flick R, Bohnenberger H, Kaderali L, Stegmann L, Cremer A, Martin M, Lohmeyer J, Michaelis M, Hornung V, Schliemann C, Berdel WE, Hartmann W, Wardelmann E, Comoglio F, Hansmann ML, Yakunin AF, Geisslinger G, Ströbel P, Ferreirós N, Serve H, Keppler OT, Cinatl J. Nat Med 23 250-255 (2017)
  2. CyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain. Yan J, Hao C, DeLucia M, Swanson S, Florens L, Washburn MP, Ahn J, Skowronski J. J Biol Chem 290 13279-13292 (2015)
  3. Low dNTP levels are necessary but may not be sufficient for lentiviral restriction by SAMHD1. Welbourn S, Strebel K. Virology 488 271-277 (2016)
  4. 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)
  5. 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)
  6. 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)
  7. 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)
  8. 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)
  9. p21 Restricts HIV-1 in Monocyte-Derived Dendritic Cells through the Reduction of Deoxynucleoside Triphosphate Biosynthesis and Regulation of SAMHD1 Antiviral Activity. Valle-Casuso JC, Allouch A, David A, Lenzi GM, Studdard L, Barré-Sinoussi F, Müller-Trutwin M, Kim B, Pancino G, Sáez-Cirión A. J Virol 91 e01324-17 (2017)
  10. The Deoxynucleoside Triphosphate Triphosphohydrolase Activity of SAMHD1 Protein Contributes to the Mitochondrial DNA Depletion Associated with Genetic Deficiency of Deoxyguanosine Kinase. Franzolin E, Salata C, Bianchi V, Rampazzo C. J Biol Chem 290 25986-25996 (2015)
  11. 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)
  12. Inhibition of Vpx-Mediated SAMHD1 and Vpr-Mediated Host Helicase Transcription Factor Degradation by Selective Disruption of Viral CRL4 (DCAF1) E3 Ubiquitin Ligase Assembly. Wang H, Guo H, Su J, Rui Y, Zheng W, Gao W, Zhang W, Li Z, Liu G, Markham RB, Wei W, Yu XF. J Virol 91 e00225-17 (2017)
  13. 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)
  14. 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)
  15. 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)
  16. 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)
  17. Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification. Yu CH, Bhattacharya A, Persaud M, Taylor AB, Wang Z, Bulnes-Ramos A, Xu J, Selyutina A, Martinez-Lopez A, Cano K, Demeler B, Kim B, Hardies SC, Diaz-Griffero F, Ivanov DN. Nat Commun 12 731 (2021)
  18. SAMHD1 deficient human monocytes autonomously trigger type I interferon. Martinez-Lopez A, Martin-Fernandez M, Buta S, Kim B, Bogunovic D, Diaz-Griffero F. Mol Immunol 101 450-460 (2018)
  19. 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)
  20. Letter Reply to SAMHD1-mediated HIV-1 restriction in cells does not involve ribonuclease activity. Ryoo J, Hwang SY, Choi J, Oh C, Ahn K. Nat Med 22 1074-1075 (2016)
  21. Short and simple sequences favored the emergence of N-helix phospho-ligand binding sites in the first enzymes. Longo LM, Petrović D, Kamerlin SCL, Tawfik DS. Proc Natl Acad Sci U S A 117 5310-5318 (2020)
  22. Structural Insights into the High-efficiency Catalytic Mechanism of the Sterile α-Motif/Histidine-Aspartate Domain-containing Protein. Li Y, Kong J, Peng X, Hou W, Qin X, Yu XF. J Biol Chem 290 29428-29437 (2015)
  23. Uncovering allostery and regulation in SAMHD1 through molecular dynamics simulations. Patra KK, Bhattacharya A, Bhattacharya S. Proteins 85 1266-1275 (2017)
  24. SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks. Kapoor-Vazirani P, Rath SK, Liu X, Shu Z, Bowen NE, Chen Y, Haji-Seyed-Javadi R, Daddacha W, Minten EV, Danelia D, Farchi D, Duong DM, Seyfried NT, Deng X, Ortlund EA, Kim B, Yu DS. Nat Commun 13 6707 (2022)
  25. 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)
  26. The crystal structure of dGTPase reveals the molecular basis of dGTP selectivity. Barnes CO, Wu Y, Song J, Lin G, Baxter EL, Brewster AS, Nagarajan V, Holmes A, Soltis SM, Sauter NK, Ahn J, Cohen AE, Calero G. Proc Natl Acad Sci U S A 116 9333-9339 (2019)
  27. 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)
  28. A molecular dynamics simulation study decodes the early stage of the disassembly process abolishing the human SAMHD1 function. Cardamone F, Iacovelli F, Chillemi G, Falconi M, Desideri A. J Comput Aided Mol Des 31 497-505 (2017)
  29. 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)
  30. 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)
  31. 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)
  32. 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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