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

DOI: 10.1016/j.chom.2015.03.004
PMID: 25856754

Authors: David Schwefel (MRC National Institute for Medical Research) , Virginie Boucherit (MRC National Institute for Medical Research) , Evangelos Christodoulou (MRC National Institute for Medical Research) , Philip  Walker (MRC National Institute for Medical Research) , Jonathan Stoye (MRC National Institute for Medical Research) , Kate Bishop (MRC National Institute for Medical Research) , Ian Taylor (MRC National Institute for Medical Research)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell Host & Microbe , VOL 17 (4) , PAGES 489 - 499

State: Published (Approved)
Published: April 2015
Diamond Proposal Number(s): 9826

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.

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Added On: 28/09/2015 16:35

Documents:
PIIS1931312815001213.pdf

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)