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.
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.
['Wu|Ying|Y|', 'Koharudin|Leonardus M I|LMI|', 'Mehrens|Jennifer|J|', 'DeLucia|Maria|M|', 'Byeon|Chang-Hyeok|CH|', 'Byeon|In-Ja L|IL|', 'Calero|Guillermo|G|', 'Ahn|Jinwoo|J|', 'Gronenborn|Angela M|AM|']
D000595:Amino Acid Sequence D000818:Animals D018360:Crystallography, X-Ray D057809:HEK293 Cells D054884:Host-Pathogen Interactions D006801:Humans D016086:Lentivirus D016180:Lentivirus Infections D062105:Molecular Docking Simulation D008969:Molecular Sequence Data D020559:Monomeric GTP-Binding Proteins D017434:Protein Structure, Tertiary D000076106:SAM Domain and HD Domain-Containing Protein 1 D016415:Sequence Alignment D054334:Viral Regulatory and Accessory Proteins D037521:Virulence Factors
restriction factor SAM domain and HD domain-containing protein 1 (SAMHD1) SIV X-ray crystallography human immunodeficiency virus (HIV) nuclear magnetic resonance (NMR) ubiquitylation (ubiquitination)