Abstract
Sterile α motif (SAM) and histidine/aspartate (HD)-containing protein 1 (SAMHD1) restricts human/simian immunodeficiency virus infection in certain cell types and is counteracted by the virulence factor Vpx. Current evidence indicates that Vpx recruits SAMHD1 to the Cullin4-Ring Finger E3 ubiquitin ligase (CRL4) by facilitating an interaction between SAMHD1 and the substrate receptor DDB1- and Cullin4-associated factor 1 (DCAF1), thereby targeting SAMHD1 for proteasome-dependent down-regulation. Host-pathogen co-evolution and positive selection at the interfaces of host-pathogen complexes are associated with sequence divergence and varying functional consequences. Two alternative interaction interfaces are used by SAMHD1 and Vpx: the SAMHD1 N-terminal tail and the adjacent SAM domain or the C-terminal tail proceeding the HD domain are targeted by different Vpx variants in a unique fashion. In contrast, the C-terminal WD40 domain of DCAF1 interfaces similarly with the two above complexes. Comprehensive biochemical and structural biology approaches permitted us to delineate details of clade-specific recognition of SAMHD1 by lentiviral Vpx proteins. We show that not only the SAM domain but also the N-terminal tail engages in the DCAF1-Vpx interaction. Furthermore, we show that changing the single Ser-52 in human SAMHD1 to Phe, the residue found in SAMHD1 of Red-capped monkey and Mandrill, allows it to be recognized by Vpx proteins of simian viruses infecting those primate species, which normally does not target wild type human SAMHD1 for degradation.
Highlights
Lentiviral viral protein X (Vpx) binding to primate SAMHD1 is under positive selection
We show that changing the single Ser-52 in human SAMHD1 to Phe, the residue found in SAMHD1 of Red-capped monkey and Mandrill, allows it to be recognized by Vpx proteins of simian viruses infecting those primate species, which normally does not target wild type human SAMHD1 for degradation
VpxSIVrcm Facilitates the Interaction between SAMHD1 and DDB1-DDB1- and Cullin4-associated factor 1 (DCAF1) via the N-terminal Domain of SAMHD1—We and others previously reported that VpxSIVsm and VpxHIV-2 preferentially interact with the CTD of SAMHD1, whereas VpxSIVrcm and VpxSIVmnd interact with the NTD of SAMHD1 (Fig. 1A) [20, 25,26,27,28]
Summary
Lentiviral Vpx binding to primate SAMHD1 is under positive selection. Results: Different Vpx protein variants interact with the N-terminal domain or the C-terminal tail of SAMHD1 in ubiquitinligase-substrate receptor complexes in a unique fashion. Sterile ␣ motif (SAM) and histidine/aspartate (HD)-containing protein 1 (SAMHD1) restricts human/simian immunodeficiency virus infection in certain cell types and is counteracted by the virulence factor Vpx. Current evidence indicates that Vpx recruits SAMHD1 to the Cullin4-Ring Finger E3 ubiquitin ligase (CRL4) by facilitating an interaction between SAMHD1 and the substrate receptor DDB1- and Cullin4-associated factor 1 (DCAF1), thereby targeting SAMHD1 for proteasome-dependent down-regulation. Strong positive selection signals at several sites in a single host gene suggest that the gene product is targeted by different viruses at multiple regions This is noted for SAMHD1, in which two separate regions, the SAM domain and the C terminus, interact with Vpx from distinct HIV/SIV strains. Our combined structural and biochemical results provide important molecular insights into how Vpx proteins from different HIV/SIV clades engage different elements in the cellular SAMHD1 protein to overcome the cell’s antiviral defense
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