Identification of the HIV-1 Vif and Human APOBEC3G Protein Interface

Cell Rep. 2015 Dec 1;13(9):1789-99. doi: 10.1016/j.celrep.2015.10.068. Epub 2015 Nov 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • APOBEC-3G Deaminase / chemistry
  • APOBEC-3G Deaminase / genetics
  • APOBEC-3G Deaminase / metabolism*
  • Binding Sites
  • HEK293 Cells
  • HIV-1 / physiology*
  • Humans
  • Immunoprecipitation
  • Molecular Dynamics Simulation
  • Mutagenesis, Site-Directed
  • Protein Interaction Maps
  • Protein Structure, Tertiary
  • Virus Replication
  • vif Gene Products, Human Immunodeficiency Virus / chemistry
  • vif Gene Products, Human Immunodeficiency Virus / genetics
  • vif Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

  • vif Gene Products, Human Immunodeficiency Virus
  • vif protein, Human immunodeficiency virus 1
  • APOBEC-3G Deaminase
  • APOBEC3G protein, human

Associated data

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