title: 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.
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.
authors.affiliation: Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Leonardus M I
authors.initials: LMI
authors.lastname: Koharudin
authors.affiliation: Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mehrens
authors.affiliation: Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Maria
authors.initials: M
authors.lastname: DeLucia
authors.affiliation: Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Chang-Hyeok
authors.initials: CH
authors.lastname: Byeon
authors.affiliation: Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: In-Ja L
authors.initials: IL
authors.lastname: Byeon
authors.affiliation: Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Calero
authors.affiliation: Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260. Electronic address: jia12@pitt.edu.
authors.forename: Jinwoo
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Department of Structural Biology and Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260. Electronic address: amg100@pitt.edu.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Gronenborn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D016086:Lentivirus / Q000502:physiology*; D016180:Lentivirus Infections / Q000378:metabolism* / Q000821:virology; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D000076106:SAM Domain and HD Domain-Containing Protein 1; D016415:Sequence Alignment; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D054334:Viral Regulatory and Accessory Proteins; D037521:Virulence Factors; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins
keywords: SAM domain and HD domain-containing protein 1 (SAMHD1); SIV; X-ray crystallography; human immunodeficiency virus (HIV); nuclear magnetic resonance (NMR); restriction factor; ubiquitylation (ubiquitination)