Molecular determinants for recognition of divergent SAMHD1 proteins by the lentiviral accessory protein Vpx.
Bottom Line: 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.
Affiliation: Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.Show MeSH
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Mentions: Despite similar overall structure and an identical mode of DCAF1 interaction (Figure S4), the SIVmnd-2 Vpx/DCAF1 assembly recognizes the SAMHD1mnd-NtD, while the HIV-2/SIVmac/SIVsmm-type Vpx/DCAF1 are specific for the SAMHD1 C terminus. Comparison of the SIVmnd-2 system presented here with the previously determined SIVsmm/DCAF1/SAMHD1-Ctd assembly (Schwefel et al., 2014) reveals the structural determinants for these fundamentally different specificities. In both complexes, a Vpx N-terminal arm and residues at the N terminus of α1 make contacts with either the amino-terminal region in SAMHD1mnd or the CtD region of SAMHD1hs. The location of this contact on the DCAF1 disk is similar in both combined ternary interfaces (Figure 6A). However, the SAMHD1mnd N terminus makes additional contacts and occupies a larger surface area on Vpx and DCAF1, 750 Å2 and 500 Å2 versus 710 Å2 and 210 Å2 for the SAMHD1hs C terminus. In addition, in the mandrill complex, the Vpx arm folds over the first 20 residues of SAMHD1mnd trapping it against DCAF1, while the human SAMHD1 C-terminal peptide associates rather peripherally to the DCAF1/Vpx interface (Figure 6A).
Affiliation: Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.