Structural basis of lentiviral subversion of a cellular protein degradation pathway

Nature. 2014 Jan 9;505(7482):234-8. doi: 10.1038/nature12815. Epub 2013 Dec 15.

Abstract

Lentiviruses contain accessory genes that have evolved to counteract the effects of host cellular defence proteins that inhibit productive infection. One such restriction factor, SAMHD1, inhibits human immunodeficiency virus (HIV)-1 infection of myeloid-lineage cells as well as resting CD4(+) T cells by reducing the cellular deoxynucleoside 5'-triphosphate (dNTP) concentration to a level at which the viral reverse transcriptase cannot function. In other lentiviruses, including HIV-2 and related simian immunodeficiency viruses (SIVs), SAMHD1 restriction is overcome by the action of viral accessory protein x (Vpx) or the related viral protein r (Vpr) that target and recruit SAMHD1 for proteasomal degradation. The molecular mechanism by which these viral proteins are able to usurp the host cell's ubiquitination machinery to destroy the cell's protection against these viruses has not been defined. Here we present the crystal structure of a ternary complex of Vpx with the human E3 ligase substrate adaptor DCAF1 and the carboxy-terminal region of human SAMHD1. Vpx is made up of a three-helical bundle stabilized by a zinc finger motif, and wraps tightly around the disc-shaped DCAF1 molecule to present a new molecular surface. This adapted surface is then able to recruit SAMHD1 via its C terminus, making it a competent substrate for the E3 ligase to mark for proteasomal degradation. The structure reported here provides a molecular description of how a lentiviral accessory protein is able to subvert the cell's normal protein degradation pathway to inactivate the cellular viral defence system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Cercocebus atys / virology
  • Crystallography, X-Ray
  • HIV / chemistry*
  • HIV / physiology*
  • Host-Pathogen Interactions
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins / chemistry
  • Monomeric GTP-Binding Proteins / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein-Serine-Threonine Kinases
  • Proteolysis*
  • SAM Domain and HD Domain-Containing Protein 1
  • Simian Immunodeficiency Virus / chemistry
  • Simian Immunodeficiency Virus / physiology
  • Ubiquitin-Protein Ligases
  • Ubiquitination
  • Viral Regulatory and Accessory Proteins / chemistry*
  • Viral Regulatory and Accessory Proteins / metabolism*
  • vpr Gene Products, Human Immunodeficiency Virus / chemistry
  • vpr Gene Products, Human Immunodeficiency Virus / metabolism

Substances

  • Carrier Proteins
  • VPX protein, Human immunodeficiency virus 2
  • VPX protein, Simian immunodeficiency virus
  • Viral Regulatory and Accessory Proteins
  • vpr Gene Products, Human Immunodeficiency Virus
  • Ubiquitin-Protein Ligases
  • DCAF1 protein, human
  • Protein-Serine-Threonine Kinases
  • SAM Domain and HD Domain-Containing Protein 1
  • SAMHD1 protein, human
  • Proteasome Endopeptidase Complex
  • Monomeric GTP-Binding Proteins

Associated data

  • PDB/4CC9