Structural insights into RNA bridging between HIV-1 Vif and antiviral factor APOBEC3G

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Great effort has been devoted to discovering the basis of A3G-Vif interaction, the key event of HIV’s counteraction mechanism to evade antiviral innate immune response. Here we show reconstitution of the A3G-Vif complex and subsequent A3G ubiquitination in vitro and report the cryo-EM structure of the A3G-Vif complex at 2.8 Å resolution using solubility-enhanced variants of A3G and Vif. We present an atomic model of the A3G-Vif interface, which assembles via known amino acid determinants. This assembly is not achieved by protein-protein interaction alone, but also involves RNA. The cryo-EM structure and in vitro ubiquitination assays identify an adenine/guanine base preference for the interaction and a unique Vif-ribose contact. This establishes the biological significance of an RNA ligand. Further assessment of interactions between A3G, Vif, and RNA ligands show that the A3G-Vif assembly and subsequent ubiquitination can be controlled by amino acid mutations at the interface or by polynucleotide modification, suggesting that a specific chemical moiety would be a promising pharmacophore to inhibit the A3G-Vif interaction.
Funding Information
  • Japan Agency for Medical Research and Development (JP18am0101076)
  • U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (R01GM118474, R01AI150478)
  • U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine

This publication has 74 references indexed in Scilit: