Molecular determinants for recognition of divergent SAMHD1 proteins by the lentiviral accessory protein Vpx

Cell Host Microbe. 2015 Apr 8;17(4):489-99. doi: 10.1016/j.chom.2015.03.004.

Abstract

The SAMHD1 triphosphohydrolase inhibits HIV-1 infection of myeloid and resting T cells by depleting dNTPs. To overcome SAMHD1, HIV-2 and some SIVs encode either of two lineages of the accessory protein Vpx that bind the SAMHD1 N or C terminus and redirect the host cullin-4 ubiquitin ligase to target SAMHD1 for proteasomal degradation. We present the ternary complex of Vpx from SIV that infects mandrills (SIVmnd-2) with the cullin-4 substrate receptor, DCAF1, and N-terminal and SAM domains from mandrill SAMHD1. The structure reveals details of Vpx lineage-specific targeting of SAMHD1 N-terminal "degron" sequences. Comparison with Vpx from SIV that infects sooty mangabeys (SIVsmm) complexed with SAMHD1-DCAF1 identifies molecular determinants directing Vpx lineages to N- or C-terminal SAMHD1 sequences. Inspection of the Vpx-DCAF1 interface also reveals conservation of Vpx with the evolutionally related HIV-1/SIV accessory protein Vpr. These data suggest a unified model for how Vpx and Vpr exploit DCAF1 to promote viral replication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / chemistry*
  • Carrier Proteins / metabolism
  • Crystallography, X-Ray
  • Host-Pathogen Interactions*
  • Mandrillus
  • Models, Molecular
  • Monomeric GTP-Binding Proteins / chemistry*
  • Monomeric GTP-Binding Proteins / metabolism
  • Protein Conformation
  • Protein Multimerization*
  • Viral Regulatory and Accessory Proteins / chemistry*
  • Viral Regulatory and Accessory Proteins / metabolism
  • Virus Replication

Substances

  • Carrier Proteins
  • VPX protein, Simian immunodeficiency virus
  • Viral Regulatory and Accessory Proteins
  • Monomeric GTP-Binding Proteins