Publication Date:
2011-11-08
Description:
SAMHD1, an analogue of the murine interferon (IFN)-gamma-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-Goutieres syndrome (AGS), an inflammatory encephalopathy characterized by chronic cerebrospinal fluid lymphocytosis and elevated levels of the antiviral cytokine IFN-alpha. 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldstone, David C -- Ennis-Adeniran, Valerie -- Hedden, Joseph J -- Groom, Harriet C T -- Rice, Gillian I -- Christodoulou, Evangelos -- Walker, Philip A -- Kelly, Geoff -- Haire, Lesley F -- Yap, Melvyn W -- de Carvalho, Luiz Pedro S -- Stoye, Jonathan P -- Crow, Yanick J -- Taylor, Ian A -- Webb, Michelle -- MC_U117512710/Medical Research Council/United Kingdom -- MC_U117533887/Medical Research Council/United Kingdom -- MC_U117565647/Medical Research Council/United Kingdom -- MC_UP_A253_1111/Medical Research Council/United Kingdom -- U117512710/Medical Research Council/United Kingdom -- U117565647/Medical Research Council/United Kingdom -- England -- Nature. 2011 Nov 6;480(7377):379-82. doi: 10.1038/nature10623.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Structure, MRC National Institute for Medical Research, London NW7 1AA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22056990" target="_blank"〉PubMed〈/a〉
Keywords:
Allosteric Regulation
;
Biocatalysis
;
Catalytic Domain
;
Crystallography, X-Ray
;
Dendritic Cells/metabolism/virology
;
Deoxyadenine Nucleotides/metabolism
;
Deoxycytosine Nucleotides/metabolism
;
Deoxyguanine Nucleotides/metabolism
;
HIV-1/*physiology
;
Humans
;
Hydrolysis
;
Models, Biological
;
Models, Molecular
;
Monomeric GTP-Binding Proteins/*chemistry/genetics/*metabolism
;
Myeloid Cells/virology
;
Nucleoside-Triphosphatase/*chemistry/genetics/*metabolism
;
Protein Structure, Tertiary
;
Reverse Transcription
;
Thymine Nucleotides/metabolism
;
Viral Regulatory and Accessory Proteins/metabolism
;
Virus Replication
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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