HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase

Nature. 2011 Nov 6;480(7377):379-82. doi: 10.1038/nature10623.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Biocatalysis
  • Catalytic Domain
  • Crystallography, X-Ray
  • Dendritic Cells / metabolism
  • Dendritic Cells / virology
  • Deoxyadenine Nucleotides / metabolism
  • Deoxycytosine Nucleotides / metabolism
  • Deoxyguanine Nucleotides / metabolism
  • HIV-1 / physiology*
  • Humans
  • Hydrolysis
  • Models, Biological
  • Models, Molecular
  • Monomeric GTP-Binding Proteins / chemistry*
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism*
  • Myeloid Cells / virology
  • Nucleoside-Triphosphatase / chemistry*
  • Nucleoside-Triphosphatase / genetics
  • Nucleoside-Triphosphatase / metabolism*
  • Protein Structure, Tertiary
  • Reverse Transcription
  • SAM Domain and HD Domain-Containing Protein 1
  • Thymine Nucleotides / metabolism
  • Viral Regulatory and Accessory Proteins / metabolism
  • Virus Replication

Substances

  • Deoxyadenine Nucleotides
  • Deoxycytosine Nucleotides
  • Deoxyguanine Nucleotides
  • Thymine Nucleotides
  • VPX protein, Human immunodeficiency virus 2
  • Viral Regulatory and Accessory Proteins
  • 2'-deoxycytidine 5'-triphosphate
  • deoxyguanosine triphosphate
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Nucleoside-Triphosphatase
  • Monomeric GTP-Binding Proteins
  • 2'-deoxyadenosine triphosphate
  • thymidine 5'-triphosphate

Associated data

  • PDB/3U1N