title: HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase.
abstract: SAMHD1, an analogue of the murine interferon (IFN)-γ-induced gene Mg11 (ref. 1), has recently been identified as a human immunodeficiency virus-1 (HIV-1) restriction factor that blocks early-stage virus replication in dendritic and other myeloid cells and is the target of the lentiviral protein Vpx, which can relieve HIV-1 restriction. SAMHD1 is also associated with Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy characterized by chronic cerebrospinal fluid lymphocytosis and elevated levels of the antiviral cytokine IFN-α. The pathology associated with AGS resembles congenital viral infection, such as transplacentally acquired HIV. Here we show that human SAMHD1 is a potent dGTP-stimulated triphosphohydrolase that converts deoxynucleoside triphosphates to the constituent deoxynucleoside and inorganic triphosphate. The crystal structure of the catalytic core of SAMHD1 reveals that the protein is dimeric and indicates a molecular basis for dGTP stimulation of catalytic activity against dNTPs. We propose that SAMHD1, which is highly expressed in dendritic cells, restricts HIV-1 replication by hydrolysing the majority of cellular dNTPs, thus inhibiting reverse transcription and viral complementary DNA (cDNA) synthesis.
authors: Division of Molecular Structure, MRC National Institute for Medical Research, London NW7 1AA, UK.
authors: David C
authors: DC
authors: Goldstone
authors: Valerie
authors: V
authors: Ennis-Adeniran
authors: Joseph J
authors: JJ
authors: Hedden
authors: Harriet C T
authors: HC
authors: Groom
authors: Gillian I
authors: GI
authors: Rice
authors: Evangelos
authors: E
authors: Christodoulou
authors: Philip A
authors: PA
authors: Walker
authors: Geoff
authors: G
authors: Kelly
authors: Lesley F
authors: LF
authors: Haire
authors: Melvyn W
authors: MW
authors: Yap
authors: Luiz Pedro S
authors: LP
authors: de Carvalho
authors: Jonathan P
authors: JP
authors: Stoye
authors: Yanick J
authors: YJ
authors: Crow
authors: Ian A
authors: IA
authors: Taylor
authors: Michelle
authors: M
authors: Webb
mesh_terms: D000494:Allosteric Regulation; D055162:Biocatalysis; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology; D003838:Deoxyadenine Nucleotides / Q000378:metabolism; D003845:Deoxycytosine Nucleotides / Q000378:metabolism; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D008954:Models, Biological; D008958:Models, Molecular; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D022423:Myeloid Cells / Q000821:virology; D043583:Nucleoside-Triphosphatase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D048348:Reverse Transcription; D000076106:SAM Domain and HD Domain-Containing Protein 1; D013942:Thymine Nucleotides / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism; D014779:Virus Replication
chemical_list: D003838:Deoxyadenine Nucleotides; D003845:Deoxycytosine Nucleotides; D003848:Deoxyguanine Nucleotides; D013942:Thymine Nucleotides; C074286:VPX protein, Human immunodeficiency virus 2; D054334:Viral Regulatory and Accessory Proteins; C024107:2'-deoxycytidine 5'-triphosphate; C029603:deoxyguanosine triphosphate; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D043583:Nucleoside-Triphosphatase; D020559:Monomeric GTP-Binding Proteins; C026600:2'-deoxyadenosine triphosphate; C024157:thymidine 5'-triphosphate