Structural basis of antagonism of human APOBEC3F by HIV-1 Vif. 2019

Yingxia Hu, and Belete A Desimmie, and Henry C Nguyen, and Samantha J Ziegler, and Tat Cheung Cheng, and John Chen, and Jia Wang, and Hongwei Wang, and Kai Zhang, and Vinay K Pathak, and Yong Xiong
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.

HIV-1 virion infectivity factor (Vif) promotes degradation of the antiviral APOBEC3 (A3) proteins through the host ubiquitin-proteasome pathway to enable viral immune evasion. Disrupting Vif-A3 interactions to reinstate the A3-catalyzed suppression of human immunodeficiency virus type 1 (HIV-1) replication is a potential approach for antiviral therapeutics. However, the molecular mechanisms by which Vif recognizes A3 proteins remain elusive. Here we report a cryo-EM structure of the Vif-targeted C-terminal domain of human A3F in complex with HIV-1 Vif and the cellular cofactor core-binding factor beta (CBFβ) at 3.9-Å resolution. The structure shows that Vif and CBFβ form a platform to recruit A3F, revealing a direct A3F-recruiting role of CBFβ beyond Vif stabilization, and captures multiple independent A3F-Vif interfaces. Together with our biochemical and cellular studies, our structural findings establish the molecular determinants that are critical for Vif-mediated neutralization of A3F and provide a comprehensive framework of how HIV-1 Vif hijacks the host protein degradation machinery to counteract viral restriction by A3F.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D011487 Protein Conformation The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). Conformation, Protein,Conformations, Protein,Protein Conformations
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000072417 Protein Domains Discrete protein structural units that may fold independently of the rest of the protein and have their own functions. Peptide Domain,Protein Domain,Domain, Peptide,Domain, Protein,Domains, Peptide,Domains, Protein,Peptide Domains
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015497 HIV-1 The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte. Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D043525 Cytosine Deaminase An enzyme which catalyzes the deamination of CYTOSINE resulting in the formation of URACIL. It can also act on 5-methylcytosine to form THYMIDINE. Cytosine Aminohydrolase,Aminohydrolase, Cytosine,Deaminase, Cytosine
D050658 Core Binding Factor beta Subunit A non-DNA binding transcription factor that is a subunit of core binding factor. It forms heterodimeric complexes with CORE BINDING FACTOR ALPHA SUBUNITS, and regulates GENETIC TRANSCRIPTION of a variety of GENES involved primarily in CELL DIFFERENTIATION and CELL CYCLE progression. Core Binding Factor beta Protein,CBFB Protein,Core Binding Factor beta,Polyomavirus Enhancer Binding Protein 2, beta Subunit
D054320 vif Gene Products, Human Immunodeficiency Virus Proteins encoded by the VIF GENES of the HUMAN IMMUNODEFICIENCY VIRUS. HIV vif Gene Product,vif Gene Products, HIV,vif Proteins, Human Immunodeficiency Virus
D057131 Immune Evasion Methods used by pathogenic organisms to evade a host's immune system. Evasion, Immune,Evasions, Immune,Immune Evasions

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