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: The extensive Vpx-DCAF1 interface comprises four contact regions with a total surface area of 1,600 Å2 (Figure 3; Table S1A). The first region comprises the C-terminal section of α2 together with first half of α3 of Vpx. On one face, apolar amino acid side chains from both α2 and α3 pack against a cluster of hydrophobic amino acids located in the “tall” loop that connects β2 to β3 in WD40 repeat 7 on the upper surface of DCAF1-CtD (Figure 3B, upper panel). On the other face, a network of hydrogen bonds and salt bridges connects Vpx residues Y62, Y65, R66, and K73 at the N terminus of α3 to acidic side chains E1191, D1092, and E1193 in the “acidic” loop of DCAF1 that intersperses WD40 repeats 7 and 1 (acidic loop, Figure 3B, lower panel). A second region of interaction involves the carboxy terminus of Vpx α3, which packs into a radial groove on the top side of DCAF1 lined by amino acids from WD40 repeats 1, 2, 4, 6, and 7. Interactions here include both the packing of hydrophobic residues as well as specific hydrogen bonding between the sidechains of Vpx Y76 and Q81 and the DCAF1 protein backbone (Figure 3C). The third binding interface involves residues at the extreme amino terminal of the Vpx N-terminal extended arm that inserts into a cavity between WD40 repeats 1 and 2 on the underside of DCAF1. Here, Vpx A2, E3 and E7 make main chain and side chain hydrogen-bonds to DCAF1 residues S1102, R1106, Y1131, and S1168 while the interposing Vpx residues A5 and P6 project into the hydrophobic cavity (Figure 3D). The remaining site of interaction involves contacts between residues in the WD40 repeat 2 of DCAF1 and residues in both Vpx α1 and α3. These include hydrophobic interactions between DCAF1 T1155 and W1156 and apolar side chains displayed on the underside of Vpx α1 and α3 and Vpx H72 on α3 that makes a hydrogen bond with mainchain carbonyl of N1135 of DCAF1 (Figure 3E).
Affiliation: Division of Molecular Structure, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.