Structural Basis of Clade-specific Engagement of SAMHD1 (Sterile α Motif and Histidine/Aspartate-containing Protein 1) Restriction Factors by Lentiviral Viral Protein X (Vpx) Virulence Factors.

摘要: Sterile α motif (SAM) and histidine/aspartate (HD)-containing protein 1 (SAMHD1) restricts human/simian immunodeficiency virus infection in certain cell types is counteracted by the virulence factor Vpx. Current evidence indicates that Vpx recruits SAMHD1 to Cullin4-Ring Finger E3 ubiquitin ligase (CRL4) facilitating an interaction between substrate receptor DDB1- Cullin4-associated (DCAF1), thereby targeting for proteasome-dependent down-regulation. Host-pathogen co-evolution positive selection at interfaces of host-pathogen complexes are associated with sequence divergence varying functional consequences. Two alternative used Vpx: N-terminal tail adjacent SAM domain or C-terminal proceeding HD targeted different variants a unique fashion. In contrast, WD40 DCAF1 similarly two above complexes. Comprehensive biochemical structural biology approaches permitted us delineate details clade-specific recognition lentiviral proteins. We show not only but also engages DCAF1-Vpx interaction. Furthermore, we changing single Ser-52 human Phe, residue found Red-capped monkey Mandrill, allows it be recognized proteins simian viruses infecting those primate species, which normally does target wild type degradation.