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

Takahide Kouno (), Satoshi Shibata, Megumi Shigematsu, Jaekyung Hyun, Tae Gyun Kim, Hiroshi Matsuo and Matthias Wolf ()
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Takahide Kouno: Okinawa Institute of Science and Technology Graduate University
Satoshi Shibata: Okinawa Institute of Science and Technology Graduate University
Megumi Shigematsu: Thomas Jefferson University
Jaekyung Hyun: Okinawa Institute of Science and Technology Graduate University
Tae Gyun Kim: Okinawa Institute of Science and Technology Graduate University
Hiroshi Matsuo: Frederick National Laboratory for Cancer Research
Matthias Wolf: Okinawa Institute of Science and Technology Graduate University

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39796-5

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