Structural Determinants of the APOBEC3G N-Terminal Domain for HIV-1 RNA Association

• Main Authors: Hirofumi Fukuda, Songling Li, Luca Sardo, Jessica L. Smith, Kazuo Yamashita, Anamaria D. Sarca, Kotaro Shirakawa, Daron M. Standley, Akifumi Takaori-Kondo, Taisuke Izumi
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2019-05-01
• Series: Frontiers in Cellular and Infection Microbiology
• Subjects: APOBEC3G; RNA; DNA; HIV-1 Vif; Structural Model; Imaging
• Online Access: https://www.frontiersin.org/article/10.3389/fcimb.2019.00129/full

APOBEC3G (A3G) is a cellular protein that inhibits HIV-1 infection through virion incorporation. The interaction of the A3G N-terminal domain (NTD) with RNA is essential for A3G incorporation in the HIV-1 virion. The interaction between A3G-NTD and RNA is not completely understood. The A3G-NTD is also recognized by HIV-1 Viral infectivity factor (Vif) and A3G-Vif binding leads to A3G degradation. Therefore, the A3G-Vif interaction is a target for the development of antiviral therapies that block HIV-1 replication. However, targeting the A3G-Vif interactions could disrupt the A3G-RNA interactions that are required for A3G's antiviral activity. To better understand A3G-RNA binding, we generated in silico docking models to simulate the RNA-binding propensity of A3G-NTD. We simulated the A3G-NTD residues with high RNA-binding propensity, experimentally validated our prediction by testing A3G-NTD mutations, and identified structural determinants of A3G-RNA binding. In addition, we found a novel amino acid residue, I26 responsible for RNA interaction. The new structural insights provided here will facilitate the design of pharmaceuticals that inhibit A3G-Vif interactions without negatively impacting A3G-RNA interactions.