title: Identification of the HIV-1 Vif and Human APOBEC3G Protein Interface.
abstract: Human cells express natural antiviral proteins, such as APOBEC3G (A3G), that potently restrict HIV replication. As a counter-defense, HIV encodes the accessory protein Vif, which binds A3G and mediates its proteasomal degradation. Our structural knowledge on how Vif and A3G interact is limited, because a co-structure is not available. We identified specific points of contact between Vif and A3G by using functional assays with full-length A3G, patient-derived Vif variants, and HIV forced evolution. These anchor points were used to model and validate the Vif-A3G interface. The resultant co-structure model shows that the negatively charged β4-α4 A3G loop, which contains primate-specific variation, is the core Vif binding site and forms extensive interactions with a positively charged pocket in HIV Vif. Our data present a functional map of this viral-host interface and open avenues for targeted approaches to block HIV replication by obstructing the Vif-A3G interaction.
authors.affiliation: The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Letko
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Thijs
authors.initials: T
authors.lastname: Booiman
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
authors.forename: Neeltje
authors.initials: N
authors.lastname: Kootstra
authors.affiliation: The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Division of Infectious Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: viviana.simon@mssm.edu.
authors.forename: Viviana
authors.initials: V
authors.lastname: Simon
authors.affiliation: The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: marcel.ooms@mssm.edu.
authors.forename: Marcel
authors.initials: M
authors.lastname: Ooms
mesh_terms: D000071480:APOBEC-3G Deaminase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D057809:HEK293 Cells; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D056004:Molecular Dynamics Simulation; D016297:Mutagenesis, Site-Directed; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D014779:Virus Replication; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D054320:vif Gene Products, Human Immunodeficiency Virus; C514847:vif protein, Human immunodeficiency virus 1; D000071480:APOBEC-3G Deaminase; C464924:APOBEC3G protein, human