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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, 4qfy, 4qfz, 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 - 4qg0 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)



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